REL B MEDIATED-REDOX REGULATION OF RADIATION THERAPY
H William
University Of Kentuckycity: Lexington country: United States (us)
Grant 5R01CA143428-02 from National Cancer Institute
Abstract: Accumulating data suggest that prostate cancers exist in an elevated state of oxidative stress and that reactive oxygen species (ROS) contribute importantly to the cytotoxic effect of ionizing radiation (IR). However, ROS also participate in cellular signaling processes leading to adaptive responses that reduce the effectiveness of radiation therapy. Thus, despite rapid advances in treatment techniques, the outcome of radiation therapy, especially for patients with tumors with unfavorable prognoses remains to be improved. The goal of this project is to identify novel mechanisms that could lead to the development of specific measures for effective treatment of aggressive prostate cancers. We have identified the alternative pathway of the redox sensitive nuclear factor kappa beta (NF-?B) as a major contributor to prostate cancer growth and progression. Preliminary data indicate that 1) aggressive prostate cancers have high nuclear RelB, a member of the alternative pathway of NF-B and manganese superoxide dismutase (MnSOD), a critical antioxidant enzyme levels; 2) suppression of RelB in androgen independent-aggressive prostate cancer cells results in reduction of interleukin 8 (IL8) levels in tumor cells and reduced tumor growth in vivo; 3) overexpression of RelB in androgen responsive prostate cancer cells results in enhanced tumor growth and production of IL8 but reduced prostate specific androgen (PSA) production; and 4) suppression of RelB nuclear translocation enhances radiation sensitivity of prostate cancer. Based on these novel and important preliminary findings, we hypothesize that RelB regulates prostate cancer response to radiation via a MnSOD dependent, NF-?B switch to activate expression of IL8 and suppress expression of PSA in prostate cancer cells. We propose that clinical testing for recurrent tumor growth should involve measuring levels of IL8 in addition to employing the standard PSA test. Combining these tests will enhance accurate cancer detection and prognosis. To test this hypothesis and validate the proof-of-concept for the combined use of IL8 and PSA as prognostic factors, three interrelated specific aims will be addressed. Aim 1 will elucidate the mechanism by which MnSOD modulates the effect of RelB on the transcription of IL8 and PSA in prostate cancer cells using biochemical and molecular biology approaches. Aim 2 will examine the role of IL8 in the protection against the effects of radiation therapy of prostate cancer. Aim 3 will determine whether serum IL8 level is a predictive marker of prostate cancer response to radiation therapy using samples from cancer patients. These mechanistic based, bench to bedside approaches should provide novel insights into the mechanisms of prostate cancer resistant to radiation therapy and may provide practical predictive measures for prostate cancer diagnostic, treatment planning and surveillance. Prostate cancer is the most frequently diagnosed cancer in men and the number of men who die from prostate cancer is unacceptably high. The results obtained from this study will provide insights into the novel mechanisms by which interleukin 8 (IL8) and prostate specific antigen (PSA) are differentially regulated and will test a proof-of-concept for using their relationship to predict the efficacy of radiation therapy for treating prostate cancer. Thus, this study will enable physicians to tailor risk-adjusted strategies for treatment of prostate cancer
Keywords: Address; Affinity Chromatography; Androgens; Animal Model; Antioxidants; base; Basic Science; bench to bedside; Binding (Molecular Function); Biochemical; Biological Assay; cancer cell; Cancer Center; Cancer Detection; cancer diagnosis; Cancer Diagnostics; Cancer Etiology; Cancer Patient; Cancer Prognosis; cancer type; Cessation of life; Clinical; Clinical Research; computerized data processing; Cultured Cells; cytotoxic; cytotoxicity; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; effective therapy; Effectiveness; Enzymes; Family; follow-up; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Human; Immunoprecipitation; improved; in vivo; inflammatory marker; insight; Interleukin-8; Ionizing radiation; Kentucky; Lead; Link; Malignant neoplasm of prostate; Malignant Neoplasms; Manganese Superoxide Dismutase; Measures; Mediating; member; men; Modeling; Molecular Biology; neoplastic cell; NF-kappa B; novel; Nuclear; Nuclear Translocation; Outcome; outcome forecast; overexpression; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Physicians; Play; Predictive Factor; Production; Prognostic Factor; Prostate; Prostate-Specific Antigen; Proteomics; public health relevance; Radiation; Radiation therapy; Radiation Tolerance; Reactive Oxygen Species; Recurrent tumor; Regulation; research clinical testing; research study; Resistance; response; Risk; Role; Sampling; Serum; Site-Directed Mutagenesis; Small Interfering RNA; Techniques; Testing; Time; Transcriptional Regulation; Translating; treatment planning; treatment strategy; tumor; tumor growth; Tumorigenicity; Universities; Visit
Relevance: Prostate cancer is the most frequently diagnosed cancer in men and the number of men who die from prostate cancer is unacceptably high. The results obtained from this study will provide insights into the novel mechanisms by which interleukin 8 (IL8) and prostate specific antigen (PSA) are differentially regulated and will test a proof-of-concept for using their relationship to predict the efficacy of radiation therapy for treating prostate cancer. Thus, this study will enable physicians to tailor risk-adjusted strategies for treatment of prostate cancer
Project start date: 2011-01-01
Project end date: 2015-11-30
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
5R01CA143428-02 (2012): $355639
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to H William
X-RAY BIOLOGICAL IRRADIATOR FOR SMALL ANIMAL AND CELL IRRADIATION
H William, Professor
Oregon Health And Science Universitycity: Portland country: United States (us)
Grant 1S10RR027376-01A1 from National Center For Research Resources
Abstract: We request funds to purchase an RS2000 biological x-ray irradiator (Rad Source Technologies, Alpharetta, GA) for small animal and cell irradiation to be run as a shared resource at Oregon Health & Science University (OHSU) in Portland, OR. The requested instrument will replace an aged cesium irradiator that has been in use at OHSU since 1978 and suffers from both severe mechanical and functional limitations. At least 15 PIs at OHSU have NIH-funded research projects that are critically dependent upon having a reliable irradiator. The RS2000 biological x- ray irradiator was chosen because of its reliability, excellent customer support and the fact that it can meet a larger range of research needs than the current instrument. Obtaining this machine will be of tremendous value to the research community at OHSU and will support current and future NIH-sponsored research projects
Keywords: aged; Animals; Biological; Cells; Cesium; Communities; Funding; Future; Health Sciences; instrument; irradiation; Mechanics; meetings; Oregon; Research; Research Project Grants; Resource Sharing; Roentgen Rays; Running; Source; Technology; United States National Institutes of Health; Universities
Project start date: 2011-04-01
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PAR-10-082
1S10RR027376-01A1 (2011): $111075
TRAINING PROGRAM IN MARINE BIOTECHNOLOGY
H William, Professor
University Of California San Diegocity: La Jolla country: United States (us)
Grant 5T32GM067550-07 from National Institute Of General Medical Sciences
Abstract: This revised Training Program application will provide students with an exceptional opportunity for cross disciplinary education and research training in the component areas of marine biotechnology, including natural products chemistry, biochemistry, genomics, pharmacology, and medicine. Moreover, this training grant will provide collaborative cross-disciplinary research mentorship through training individual students in different laboratories in multiple departments on the UCSD campus as well as the Salk Institute and J. Craig Venter Institute. To accomplish this mission, the TP has the following objectives (1) to provide new course offerings that create a unique curriculum on the UCSD campus that is the intellectual foundation for research in the multidisciplinary field of Marine Biotechnology (2) to provide a stimulating series of seminars by leaders in the field of Marine Biotechnology, and to develop skills in our trainees through special opportunities to arrange and host these visiting speakers (3) to provide Industrial Internships that broaden the educational base and technology perspective of our graduates (4) to provide opportunities to our trainees that develop their research presentation skills through an annual symposium, participation in various research and journal clubs, and participation at national and international conferences (5) to provide competitively awarded financial support to especially meritorious trainees for a 2-year period in recognition of their superior research efforts and talents. The rationale for this training program is the need to train students for the biotechnology industry as well as for academia with an integrated knowledge of marine systems and their unique chemical, biochemical, and genetic attributes. To our knowledge, this broad training platform is not offered at any other institution in the US, and thus our graduates are sought after to fill a unique need in industry and academia. The training is proposed for 6 predoctoral trainees in the first two years and 8 predoctoral trainees in the latter three years of the renewal period, supplemented by 2 or more university-supported trainees, to support students in their second and third year of their 5-year Ph.D. programs. The assembly of this faculty and research strength under the auspices of the TP in Marine Biotechnology is helping to create a unique, internationally recognized educational and research program at UCSD. RELEVANCE Marine organisms are an exceptional source of natural products with useful medical properties. Fully accessing these natural products is enhanced by an integrated chemical and genetic approach, which is inherently complex and multidisciplinary. UCSD has a unique assembly of academic and research programs which can train the next generation of scientists in these areas
Keywords: Biotechnology; Marines; Training Programs
Project start date: 2003-07-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-08-226
5T32GM067550-07 (2011): $143856
RESEARCH AND MENTORING IN PSYCHOSOCIAL ONCOLOGY
H William, Professor
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 5K05CA108955-08 from National Cancer Institute
Abstract: This K05 award is requested to allow William H. Redd, PhD, to devote his full-time effort to mentoring postdoctoral trainees and junior faculty and to conduct research in cancer prevention and control. Mentoring will include I) one-on-one writing and discussion sessions in which research ideas, papers and research protocols are reviewed and revised; 2) didactic research seminars in which substantive material relevant to cancer prevention and control is presented and discussed; 3) work-in-progress sessions in which research reports written by trainees and/or by faculty are reviewed; 4) trainee-led journal club sessions in which trainee selected published research manuscripts are reviewed/discussed; and 5) research seminars in which outside experts in cancer prevention and control present their work and consult on trainee and faculty research proposals and studies. Mentoring sessions and seminars will be scheduled on a weekly or biweekly basis. The primary goal is to enable trainees and junior faculty to become independent researchers and mentors in cancer prevention and control. Research conducted during the tenure of the proposed award will reflect an overall broadening of my interests within the area of cancer prevention and control. I will specifically investigate 1) cognitive-behavior therapy in the treatment of anxiety-related adjustment problems in adult long term survivors of BMT/SCT in the treatment of cancer; and 2) culturally targeted patient navigation to increase participation in colorectal cancer screening among medically under-served minority groups. Each of these topics will be explored through separate R-01 funded randomized clinical trials. I also propose to address my growing appreciation for the importance of disseminating research findings in cancer prevention and control. I plan to implement a R-25E training program designed to disseminate the intervention methods we have developed. The program will train health care professionals to implement cognitive-behavioral therapy with cancer survivors. Trainees will participate in all aspects/phases of the proposed research. RELEVANCE The importance of exploring the role of behavioral factors in cancer has been highlighted in two reports prepared for the National Cancer Institute by the Cancer Prevention Program Review Group and the Cancer Control Review Group. These reports also note the need to develop a cadre of research scientists with the necessary interdisciplinary skills to address these complex issues. The research and mentoring that Dr. Redd plans to carry out during the course of the proposed K-05 directly addresses these important needs
Keywords: Address; Adult; Anxiety; Area; Award; base; Behavioral; Cancer Control; cancer prevention; Cancer Survivor; cancer therapy; Cognitive Therapy; colorectal cancer screening; Complex; Consult; design; Doctor of Philosophy; Faculty; Funding; Goals; Health Professional; Institute for Cancer Prevention; interest; Intervention; Journals; Long-Term Survivors; Malignant Neoplasms; Manuscripts; Mentors; Methods; Minority Groups; National Cancer Institute; oncology; Paper; Patients; Phase; Prevention program; Program Review Group; programs; Protocols documentation; psychosocial; Publishing; Randomized Clinical Trials; Reporting; Research; Research Personnel; Research Proposals; research study; Role; Schedule; Scientist; Senior Scientist Award; skills; Time; Training; Training Programs; Work; Writing
Project start date: 2004-09-10
Project end date: 2014-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PAR-05-145
5K05CA108955-08 (2011): $165634
FUNCTIONAL IMAGING OF GANGLION CELLS IN THE LIVING MAMMALIAN EYE
H William, Professor
University Of Rochestercity: Rochester country: United States (us)
Grant 1R01EY021166-01 from National Eye Institute
Abstract: The primate retina contains more than 17 classes of ganglion cells, but the contribution to vision of all but a few of these classes is unknown. This large gap in understanding is due to the fact that most ganglion cell types form such sparse mosaics that it is difficult with a single microelectrode or even an array of microelectrodes to record from enough cells of any given class to characterize its functional role. Another limitation of microelectrode technology is that the recording process is invasive, requiring penetration of the globe or, in the case of an eyecup preparation, enucleation of the eye. This precludes the ability to repeat experiments on the same cells and limits behavioral experiments on the same animals in which electrical responses have been obtained. However, rapid advances are being made in the development of reporter molecules that allow optical monitoring of the electrical responses of single neurons with multiphoton fluorescence. Moreover, the recent development of adaptive optics for correcting the eye´s aberrations now makes it possible to image individual ganglion cells at ~ 2 micron resolution in the living primate eye. We will develop a new technology for retinal physiology, Functional Adaptive-optics Cellular Imaging in the Living Eye (FACILE) that combines adaptive optics in vivo imaging with optical recording to map the electrical activity of each of the several hundred ganglion cells simultaneously in a patch of monkey retina. We will use viral transduction to insert a genetically encoded calcium indicator (GCaMP3) into ganglion cells, exploring two delivery methods to further improve viral transduction of macaque ganglion cells intravitreal injection of adeno- associated virus (AAV) in collaboration with John Flannery at UC, Berkeley and retrograde transport of pseudotyped equine anemia immunodeficiency virus (EAIV) injected into retino-recipient nuclei in collaboration with Ed Callaway at the Salk Institute. The development of FACILE will accelerate the complete characterization of the many pathways from the retina to the brain and will reveal the full contribution the retina makes to visual information processing. We will undertake early development of FACILE in a mouse model, and deploy the mature technology in monkey retina. In years 4-5, we will demonstrate the value of the approach by resolving the long-standing debate about whether the macaque retina contains direction-selective neurons, such as those that have been identified in the retinas of several other mammals. The primate retina contains more than 17 classes of ganglion cells, but the contribution to vision of all but a few of these classes is unknown, a consequence of the weakness of existing physiological methodology for understanding novel cell types. This project will develop a new technology for retinal physiology, Functional Adaptive-optics Cellular Imaging in the Living Eye (FACILE) that combines adaptive optics in-vivo imaging with optical recording to map the electrical activity of each of the several hundred ganglion cells simultaneously in a patch of monkey retina. The novel approach will be used to examine the possibility that among the unknown ganglion cell classes are directionally selective ganglion cells, as in other mammalian retinas. This methodology will accelerate our analysis of the full contribution of the many pathways from retina to brain in primate visual information processing
Keywords: adaptive optics; Address; adeno associated virus group; Adeno-Associated Viruses; Anemia; Animals; base; Behavioral; Brain; calcium indicator; cell imaging; Cell Nucleus; cell transduction; cell type; Cells; cellular imaging; cellular transduction; Collaborations; density; Dependovirus; Development; Electrodes, Miniaturized; Electrophysiology; Electrophysiology (science); Encephalon; Encephalons; Equine; Equine Species; Equus caballus; Equus przewalskii; experiment; experimental research; experimental study; Eye; Eye Development; Eye Enucleation; eye morphogenesis; Eyeball; Fluorescence; Functional Imaging; gangliocyte; ganglion cell; Ganglion Cells (Retina); Gene Delivery; Grant; Horse, Domestic; Horses; hypoimmunity; Image; imaging; immune deficiency disorder; immunodeficiency; Immunodeficiency Disorder; Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; Immunological Deficiency Syndromes; improved; In Vitro; in vivo; Individual; information processing; Injection of therapeutic agent; Injections; Institutes; Life; Macaca; Macaque; Mammalia; Mammals; Mammals, General; Mammals, Mice; Mammals, Primates; Mammals, Rodents; Maps; Method LOINC Axis 6; Methodology; Methods; Mice; Microelectrodes; Monitor; Monkeys; Motion; mouse model; Murine; Mus; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; neuronal; Neurons; Neurophysiology / Electrophysiology; new approaches; new technology; novel; novel approaches; novel strategies; novel strategy; Nucleus; ocular development; Optics; pathway; Pathway interactions; Penetration; Physiologic; Physiologic Imaging; Physiological; Physiology; Preparation; Primates; Process; public health relevance; Reporter; Reporting; research study; Resolution; response; Retina; Retinal; retinal ganglion; Retinal Ganglion Cells; retrograde transport; Rodent; Rodentia; Rodentias; Role; Sight; social role; Staging; Stimulus; Technology; Testing; transduced cells; transduction efficiency; Viral; Virus; Viruses, General; Vision; Visual; visual information
Relevance: The primate retina contains more than 17 classes of ganglion cells, but the contribution to vision of all but a few of these classes is unknown, a consequence of the weakness of existing physiological methodology for understanding novel cell types. This project will develop a new technology for retinal physiology, Functional Adaptive-optics Cellular Imaging in the Living Eye (FACILE) that combines adaptive optics in-vivo imaging with optical recording to map the electrical activity of each of the several hundred ganglion cells simultaneously in a patch of monkey retina. The novel approach will be used to examine the possibility that among the unknown ganglion cell classes are directionally selective ganglion cells, as in other mammalian retinas. This methodology will accelerate our analysis of the full contribution of the many pathways from retina to brain in primate visual information processing
Project start date: 2011-02-01
Project end date: 2014-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-10-067
1R01EY021166-01 (2011): $681529
ICBG: "TRAINING, CONSERVATION AND DRUG DISCOVERY USING PANAMANIAN MICROORGANISMS
H William, Professor
Smithsonian Institutioncity: Arlington country: United States (us)
Grant 5U01TW006634-09 from Fogarty International Center
Abstract: The over-arching goal of this work is to discover new lead compounds from Panamanian microorganisms for the treatment of cancer, CNS disorders, tropical diseases, and agricultural pests, employing a spectrum of innovative as well as traditional bioassays. This pursuit will be inextricably connected to the development of scientific training and capacity building in a biodiversity-rich yet economically-developing country, and will foster tangible results in biodiversity conservation and infrastructure development. The specific aims of this proposal which will allow us to reach these goals are 1) Use ecological concepts to guide the collection and culture of endophytic fungi, cyanobacteria and other heterotrophic bacteria within the biodiversity-rich country of Panama, 2) Produce extracts of these collected and cultured materials and prefractionate these by appropriate techniques to produce reduced complexity screening units which have active ingredients in increased titer, 3) Through efforts of personnel in AP2 plus our collaborators, to perform biological screens of extracts, prefractionated extracts, and pure compounds in the following therapeutic areas Cancer, Central Nervous System biology, Agriculture, and Tropical diseases (malaria, leishmania and Chagas´ disease), 4) Utilize an integrated approach of taxonomy, computer databases, and LC-MS data to rapidly and efficiently dereplicate known and nuisance compounds at early stages in the discovery process, 5) Isolate active compounds identified in the above assay areas using bioassay-guided approaches, and to characterize these substances using efficient and modern spectroscopic methods, 6) Inventory the biodiversity of terrestrial plants and marine algae in Panama, and to continue to build the permanent floral collections in Panama, 7) Evolve and maintain the formal contracts between all of the participants in this program to address intellectual property rights, promote equitable sharing of benefits, and to facilitate broad access to the data and results of these research endeavors, 8) Help build the scientific infrastructure and expertise necessary to support a sustainable drug discovery program based in Panama, and 9) Integrate our drug discovery and conservation efforts to develop innovative new economic products from the biodiverse marine and terrestrial habitats of Panama. This proposal seeks to discover new medicines from Panama´s rich biodiversity of terrestrial and marine microorganisms. The focus of our discovery efforts are new treatments for cancer, CNS disorders, and tropical diseases as well as agricultural chemicals
Keywords: Address; Agriculture; Agrochemicals; Algae; Area; Bacteria; base; benefit sharing; Biodiversity; Biological; Biological Assay; Biomedical Research; Cancer cell line; cancer therapy; Central Nervous System Diseases; Chagas Disease; Collaborations; Collection; Community Outreach; Computers; Contracts; Country; Cyanobacterium; Data; Databases; Developing Countries; Development; drug discovery; Economics; endophytic fungi; Equipment and supply inventories; Fostering; fungus; Goals; Habitats; High Pressure Liquid Chromatography; Human Resources; infrastructure development; innovation; Insecta; Institutes; Intellectual Property; Island; Lead; Leishmania (genus); Leishmaniasis; Malaria; Malignant Neoplasms; Marines; Medicine; Methods; microorganism; Panama; Panamanian; Participant; Plants; Process; programs; Property Rights; Research; Research Infrastructure; Sampling; Screening procedure; Site; Staging; Structure; Systems Biology; Taxonomy; Techniques; Therapeutic; Training; Transcription Factor AP-2 Alpha; Tropical Disease; Work
Project start date: 2003-09-27
Project end date: 2013-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: RFA-TW-08-003
5U01TW006634-09 (2011): $516936
3U01TW006634-09S1 (2011): $200000
MOLECULAR BASIS OF DIFFERENTIATION AND DEVELOPMENT
H William
University Of Texas Md Anderson Can Ctrcity: Houston country: United States (us)
Grant 5T32HD007325-25 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: The objectives of this training program are to provide pre- and postdoctoral trainees with high quality training in fundamental aspects of cell growth, differentiation, and development, and to offer an interactive environment that extends beyond the individual laboratory experience. The program is designed to expose trainees to a wide range of research subjects and experimental systems that will be essential for their future career advancement. These include embryo development, regulation of gene expression, cellular growth, differentiation and survival, chromatin structure and remodeling, and biophysical and structural analysis of macromolecules associated with cell regulation. Program faculty members are drawn from the Department of Biochemistry and Molecular Biology (seventeen) and the Department of Molecular Genetics (two) at The University of Texas M. D. Anderson Cancer Center. The Program benefits greatly from its location within the multi-institutional Texas Medical Center, a progressive and integrated graduate school, and a strong commitment from the M. D. Anderson leadership to educating future biomedical scientists. Predoctoral trainees begin the program in their second year and remain until the end of their fourth year. Students take formal coursework in biomedical ethics, experimental genetics, biochemistry and molecular biology, biomedical statistics, eukaryotic gene expression, developmental biology, and a series of seminar courses designed to develop skills in oral presentation. Postdoctoral trainees receive three year appointments and must document training in biomedical ethics and submit at least one postdoctoral fellowship application during their first year. Four pre- and one postdoctoral trainees participate in the program. A trainee orientation each fall, student rotation talks, Blaffer endowed lecture series, research and journal clubs, and an annual spring retreat are all designed to foster interactions and collaborations. A monthly trainee workshop focuses on the future of biomedical research. Trainees are selected from a large pool of well qualified applicants and many trainees advance to prestigious positions at major academic institutions following their training
Keywords: base; Development; Molecular
Project start date: 1986-07-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
5T32HD007325-25 (2011): $172419
REDOX MODULATION OF PROSTATE CANCER
H William, Radiation Oncology
University Of Kentuckycity: Lexington country: United States (us)
Grant 5R01CA115801-05 from National Cancer Institute
Abstract: The nuclear factor kappa beta (NF-kB), a redox-sensitive transcription factor, is well established as a regulator of genes coding for both proapoptosis and prosurvival proteins. It has been shown that hormone-independent prostate cancer has a high constitutive level of NF-kB and activation of NF-kB by cancer therapeutic agents can blunt the activity of these agents to cause cancer cell death. The goal of this project is to gain insight into an NF-kB mediated mechanism leading to intrinsic radiation resistance and to identify novel approaches that can be used to improve the treatment of prostate cancer. Our initial data demonstrate that androgen-independent prostate cancer has high levels of selected members of the NF-kB family and its prosurvival NF-kB target gene products including the primary antioxidant enzyme, manganese superoxide dismutase, and the antiapoptotic protein, BclXL. We also found that radiation induced activation of NF-kB in a two-wave pattern. We hypothesize that tumor cells with high levels of constitutive NF-kB will be sensitive to inhibition of the NF-kB mediated cytoprotective pathway and modulation of this pathway can improve the radiation response of aggressive prostate cancer. Parental PC-3 and its NF-kB mutant derived cell lines will be used as models for androgen-independent prostate cancer cells. Parental LNCaP and its corresponding derivatives will be used as models for androgen-dependent prostate cancer cells. Well characterized PC-3 derived as well as LNCaP derived prostate cancer cell lines will be studied in vitro and in vivo. Five-weeks-old male athymic nude mice will be used as hosts of human prostate cancer cells by orthotopic implantation in the prostate glands. Specific aim 1 is designed to identify specific members of the NF-kB family that play an important role in high intrinsic radioresistance of aggressive prostate cancer cells. Specific aim 2 is designed to test the concept that selective modulation of NF-kB or redox-based intervention can be used to enhance radiation sensitivity. Specific aim 3 is designed to validate the results from Specific aim 2 in an experimental therapeutic setting. Accomplishment of this study will enhance our understanding of the mechanisms by which members of the NF-kB family participate in cell survival. This information can serve as a rationale for the development of selective approaches that might eventually translate into significant clinical benefit
Keywords: androgen independent prostate cancer; Androgens; Antioxidants; base; Binding Sites; cancer cell; Cancer Etiology; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; Clinical; Clinical Treatment; Code; Data; design; Development; direct application; Dominant-Negative Mutation; Dose; Enhancer Elements (Genetics); Enzymes; Family; Family member; Free Radicals; Gene Targeting; Genes; Genetic Transcription; Goals; Growth; Hormones; Human; Implant; implantation; improved; In Vitro; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; insight; Interruption; Intervention; LNCaP; Location; male; Malignant neoplasm of prostate; Malignant Neoplasms; Manganese Superoxide Dismutase; Mediating; member; men; Modeling; Monitor; Mus; mutant; Nature; neoplastic cell; NF-kappa B; novel strategies; Nude Mice; overexpression; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Pattern; PC3 cell line; Play; prevent; Process; Promotor (Genetics); Prostate; Proteins; Radiation; radiation effect; radiation resistance; Radiation Tolerance; Reactive Oxygen Species; Regulator Genes; research study; Resistance; response; RNA; Role; Signal Transduction; survivin; Testing; Therapeutic; Therapeutic Agents; Time; transcription factor; Translating; tumor; Tumor Necrosis Factor Ligand Superfamily Member 6
Project start date: 2007-08-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
5R01CA115801-05 (2011): $243022
ANTIBIOTIC DOSING IN CONTINUOUS DIALYSIS
H William, Associate Staff
Cleveland Clinic Lerner Col/med-cwrucity: Cleveland country: United States (us)
Grant 5R21DK088045-02 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The long-term objective of this project is to improve outcomes in dialysis-dependent acute kidney injury through meticulous attention to dialytic therapy. This goal is clinically crucial as survival in acute kidney injury remains poor and absolute numbers of cases increase each year. The work in this proposal will determine whether there is a need for a large-scale, expensive clinical trial optimizing antibiotic dosing in patients with acute kidney injury who receive continuous dialysis. First, it will measure actual drug levels in patients receiving continuous dialysis in the ICU and compare these levels to standard adequacy criteria. Second, it will calculate basic pharmacokinetic parameters for each of five antibiotics in this critically ill population, and estimate whether patient data, such as weight and dialysis prescription, can be used to guide drug dosing, or whether individualized therapeutic drug monitoring is necessary to meet target antibiotic concentrations. Finally, it tests whether a waste product, used dialysate, can be used as a surrogate for blood in measuring antibiotic levels. Taken together, this pilot and feasibility project will answer whether a worrisome clinical question needs further investigation, will define whether therapeutic drug monitoring is needed in this population for optimal dosing, and test a strategy for rapid and inexpensive drug assays in this population. Kidney failure is increasingly common in the United States as the population grows and survival in other illnesses improves. Kidney failure that complicates another illness or procedure, such as a heart attack or a cancer surgery, called "acute kidney injury" or AKI, has very high mortality. Choosing the best dose of an antibiotic for such a patient is difficult because the body´s excretion of the drug is often changed, and the dialysis itself may also remove some drug. In this study, we look at patients who are receiving dialysis as treatment for AKI and who are also receiving any of five commonly used antibiotics. We will study whether the patients are getting enough antibiotic by comparing antibiotic levels in their blood to published guidelines for effective treatment of various infective agents
Keywords: Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Amines; Aminoglycosides; Antibiotics; Antihypertensive Agents; antimicrobial; Area; Area Under Curve; Attention; beta-Lactams; Biological Assay; Blood; Blood flow; California; cancer surgery; Carbapenems; Case Study; Categories; Catheters; Cause of Death; Ceftazidime; Ciprofloxacin; Clinical; clinical effect; clinical efficacy; clinical practice; Clinical Trials; Critical Illness; Data; Data Reporting; Devices; Dialysis procedure; Dose; drug clearance; Drug Kinetics; Drug Monitoring; effective therapy; Enrollment; Epidemiologic Studies; Equipment; Excretory function; Failure (biologic function); Feasibility Studies; Filtration; Fluconazole; Fluoroquinolones; Future; Goals; Guidelines; High Pressure Liquid Chromatography; Hospitals; Imipenem; improved; Incidence; Infection; Infusion procedures; Investigation; Kidney; Kidney Failure; Killings; Laboratory Research; Literature; Measures; meetings; Minimum Inhibitory Concentration measurement; Modeling; Mortality Vital Statistics; Myocardial Infarction; Organ; Outcome; Paper; Patients; Persons; Pharmaceutical Preparations; Pilot Projects; Piperacillin-Tazobactam; Plasma; Population; Preparation; Prevalence; Procedures; Process; public health relevance; Publishing; Recommendation; Renal dialysis; Reporting; Resources; response; sample collection; Sampling; San Francisco; secondary outcome; Surface; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; United States; Vancomycin; Waste Products; Weight; Work
Relevance: Kidney failure is increasingly common in the United States as the population grows and survival in other illnesses improves. Kidney failure that complicates another illness or procedure, such as a heart attack or a cancer surgery, called "acute kidney injury" or AKI, has very high mortality. Choosing the best dose of an antibiotic for such a patient is difficult because the body´s excretion of the drug is often changed, and the dialysis itself may also remove some drug. In this study, we look at patients who are receiving dialysis as treatment for AKI and who are also receiving any of five commonly used antibiotics. We will study whether the patients are getting enough antibiotic by comparing antibiotic levels in their blood to published guidelines for effective treatment of various infective agents
Project start date: 2010-07-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-09-164
5R21DK088045-02 (2011): $155430
H William, Professor
Brown Universitycity: Providence country: United States (us)
Grant 5R01EY010923-25 from National Eye Institute
Abstract: The long-term objective of this project is to develop a dynamical model of visually controlled locomotor behavior, which can be used to simulate visual mobility problems and predict paths of locomotion in everyday environments. The research pursues two closely related problems First, the behavioral dynamics of locomotion, or how safe paths of locomotion are generated through a complex changing environment; second, the control laws for locomotion, or how this behavior is guided by perceptual control strategies based on multisensory information. In previous research, we developed a dynamical model of four elementary locomotor behaviors (a) steering to a stationary goal, (b) avoiding a stationary obstacle, (c) intercepting a moving target, and (d) avoiding a moving obstacle. Using virtual reality techniques in freely-walking participants, we empirically tested each component, and then studied how the elementary behaviors are integrated in more complex situations. We found that linear combinations of the components successfully predict human paths with various pairs of goals and obstacles, such as a moving target with a stationary obstacle, and even with pairs of participants in a pursuit/evasion task; however, attentional factors appear to play a role with multiple obstacles. In a second set of studies, we tested the contributions of optic flow, egocentric direction, and gaze/head/body alignment to online steering control and visual-locomotor adaptation. The specific aims of the proposed research are to pursue locomotor interactions between pedestrians, map out multisensory contributions to perceptual control strategies, and apply the model to simulate visual impairments and mobility problems. We will manipulate visual information during walking using virtual environments presented in a head-mounted display, podokinetic information by locomotor adaptation, vestibular information by galvanic stimulation, and neck proprioception by muscle vibration. Four studies are proposed (1) Pedestrian interactions will investigate locomotor interactions between pedestrians, including a pair of participants, a participant interacting with a simulated virtual agent, a participant interacting with a crowd of virtual agents, and naturalistic studies of pedestrian traffic flow. (2) Multisensory control strategies will test the contributions of visual, podokinetic, vestibular, and proprioceptive information to steering control. (3) Complex behaviors will extend the model to incorporate attentional factors, speed control, and address the question of "online" control or advance path planning. (4) Modeling peripheral field loss will empirically test and seek to model the effects of tunnel vision and homonymous hemianopsia on mobility. PUBLIC HEALTH RELEVANCE The results will contribute to basic knowledge about the visual control of locomotion and apply it to clinical understanding of visual mobility problems in disease and aging. A working model of locomotor behavior would allow us to predict individual paths of locomotion or pedestrian traffic in everyday situations, simulate specific visual impairments and mobility problems, inform architectural planning to facilitate mobility, and evaluate potential remediations
Keywords: 0-11 years old; Address; Affect; Aging; base; Behavior; Behavioral; Biological Models; Child; Child Youth; children; Children (0-21); Clinical; Complex; computer based prediction; Crowding; Data; disability; Disease; disease/disorder; Disorder; Environment; experiment; experimental research; experimental study; Eye; Eyeball; gaze; Goals; Grant; hazard; Head; Health; Homonymous Hemianopia; Homonymous Hemianopsias; Human; Human, Child; Human, General; Individual; Intercept; Intervention; Intervention Strategies; interventional strategy; Investigation; Knowledge; Laws; Linear Models; Locomotion; Locomotor adaptation; Man (Taxonomy); Man, Modern; Maps; Methods and Techniques; Methods, Other; Minor; Model System; Modeling; Models, Biologic; motor control; multisensory; Muscle; Muscle Tissue; Neck; optic flow; Partial Sight; Participant; Patients; Performance; Peripheral; Play; predictive modeling; Proprioception; remediation; Research; Research Institute; research study; Role; Senescence; senescent; Sight; Simulate; simulation; social role; Specific qualifier value; Specified; Speed; Speed (motion); Techniques; Testing; theories; Time; trafficking; Training; Vibration; vibration; Vibration - physical agent; virtual; virtual reality; Vision; Vision research; Vision, Diminished; Vision, Low; Vision, Reduced; Vision, Subnormal; Visual; visual control; Visual Fields; Visual impairment; visual information; visual motor; visually impaired; visuomotor; Walking; Work; youngster
Relevance: Relevance The results will contribute to basic knowledge about the visual control of locomotion and apply it to clinical understanding of visual mobility problems in disease and aging. A working model of locomotor behavior would allow us to predict individual paths of locomotion or pedestrian traffic in everyday situations, simulate specific visual impairments and mobility problems, inform architectural planning to facilitate mobility, and evaluate potential remediations. 14
Project start date: 1985-06-01
Project end date: 2013-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PA-07-070
5R01EY010923-25 (2011): $433475
Sponsored Links Excellgen http://Excellgen.com
MOLECULAR BIOLOGY AND STRUCTURE OF A DNA REPLICASE
H William, Professor
Yale Universitycity: New Haven country: United States (us)
Grant 5R01GM063276-10 from National Institute Of General Medical Sciences
Abstract: The long term objectives of this proposal are to understand the basis for the high fidelity exhibited by replicative DNA polymerases (DNA pols). Specifically we want to (i) understand how the dynamics of conformational changes exhibited by DNA pols affect base discrimination; (ii) follow structural changes in DNA pols and their "fidelity" mutants during DNA synthesis with correct (R) and incorrect (W) incoming dNTPs; (iii) identify transient intermediates in the reaction pathway for primer extension with R and W dNTPs using wild type (wt) and "fidelity" mutants of DNA pols; (iv) identify structural features of the RB69 pol "fidelity" mutants that are responsible for the high level of misincorporation exhibited by these mutants; (v) identify the chemical features of a nascent base-pair that allow the incoming dNTP to be inserted with high efficiency. To reach these goals we will determine rates of conformational changes when the wt and mutant pols encounter dNTPs that harbor either non-complementary bases or nucleobase analogs. For this purpose we will employ; (i) stopped-flow fluorescence with dye labeled polymerases and with fluorescent base analogs in the template strand of primer-templates (P/Ts) in ensemble-averaged and in single-molecule experiments; (ii) Single-Molecule Fluorescence Energy Transfer (smFRET) to investigate the dynamics of the nucleotide addition cycle with the aim of capturing transients in the reaction pathway; (iii) rapid chemical quench experiments to obtain rates of product formation; (iv) X-ray crystallography to determine structural changes that occur when wt dNTPs or dNTPs containing base analogs are bound in ternary complexes (v) polychromatic, time-resolved X-ray crystallography using Laue diffraction to visualize changes in the structure of intermediates during the nucleotidyl transfer reaction. This can be accomplished by using "caged" dNTPs that can be converted to dNTP substrates by photolysis. We are using RB69 pol, a member of the B family (which includes two human DNA pols, pol alpha and pol delta) so that information acquired from RB69 pol and its mutants should be relevant to human DNA pols as well. Taken together, the results of these investigations will contribute to a better understanding of diseases that involve malfunctioning of DNA pols required for replication and repair. They will also provide the basis for devising therapeutic strategies to curtail or halt DNA replication and/or repair which could cripple malignant cells. This information could also be helpful in combating infections caused by viruses, bacteria or parasites. Narrative DNA polymerases are responsible for copying and repairing the genomes of all living organisms. If they malfunction disease and even death may follow. Thus it is important to understand how they function to faithfully replicate DNA so that therapeutic intervention, when necessary can be effective
Keywords: ing; Affect; analog; Attention; Bacteria; Bacteriophages; base; Base Pairing; Behavior; Binding (Molecular Function); Bypass; cancer cell; Cessation of life; Chemicals; Chemistry; combat; Complex; design; Discrimination (Psychology); Disease; DNA; DNA biosynthesis; DNA Damage; DNA replicase; DNA-Directed DNA Polymerase; Dyes; Energy Transfer; Exhibits; expectation; Family; Fluorescence; Fluorescence Microscopy; Fluorescence Resonance Energy Transfer; Frequencies (time pattern); Gene Targeting; Genome; Goals; Hot Spot; human DNA; In Vitro; in vivo; Infection; Investigation; Kinetics; Label; Lesion; Life; Location; member; Molecular Biology; Molecular Structure; Monitor; mutant; Mutation; nucleobase analog; nucleoside analog; Nucleotides; Organism; Parasites; Pathway interactions; photolysis; Polymerase; Positioning Attribute; Primer Extension; Process; Progress Reports; Property; Proteins; public health relevance; Reaction; repaired; Research Design; research study; Resolution; Single base substitution; single molecule; single-molecule FRET; Site; stoichiometry; stopped-flow fluorescence; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Time; time use; Virus; X-Ray Crystallography
Relevance: Narrative DNA polymerases are responsible for copying and repairing the genomes of all living organisms. If they malfunction disease and even death may follow. Thus it is important to understand how they function to faithfully replicate DNA so that therapeutic intervention, when necessary can be effective
Project start date: 2001-04-01
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01GM063276-10 (2011): $327690
ENDOTHELIAL CELL DERIVED FACTORS FOR RADIATION INDUCED BONE MARROW SYNDROME
H William, Professor
Albert Einstein Col Of Med Yeshiva Univcity: Bronx country: United States (us)
Abstract: The hematopoietic system is exquisitely sensitive to radiation damage. Otherwise survivable doses of acute radiation will cause irreversible bone marrow failure and death in humans. To date, the only curative approach is cell replacement therapy using transplanted bone marrow or peripheral blood hematopoietic progenitor cells. However it is not feasible to use this therapy for treating acute radiation induced injury. Alternative approaches that are focused on identifying methods to mitigate radiation induced cell death and promote host hematopoietic regeneration are urgently needed. Initial studies from our laboratory revealed that factors produced by blood vessel derived endothelial cells can regenerate hematopoiesis and prevent death after exposure to gamma radiation. This experimental system provides a novel approach to identify the cellular and molecular mechanisms responsible for the radioprotection of bone marrow. The goal ofthis proposal is to exploit this model to identify the factors and signals elaborated by endothelial cells that mediate the regeneration ofthe hematopoietic system. To accomplish this we propose to develop strategies to augment hematopoietic recovery following bone marrow lethal doses of radiation. The first aim will identify the diverse cellular mechanisms responsible for endothelial cell mediated radioprotection ofthe hematopoietic system. In the second aim we will determine the molecular mechanisms that govern hematopoietic regeneration and identify candidate radioprotective factors. RNA sequencing will be used to obtain non-biased patterns of gene expression associated with key transcriptional responses that mediate hematopoietic cell radioprotection. The ultimate goal ofthis research is to identify therapeutic factors that can enhance the regeneration of the hematopoietic system following radiation injury
Keywords: Acute; Apoptosis; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; Brain; Cell Count; Cell Death; Cell physiology; Cell Therapy; Cell Transplantation; Cell Transplants; Cells; Cessation of life; Clinical; Defect; Dose; Endothelial Cells; Exhibits; experience; Exposure to; gain of function; Gamma Rays; Gene Expression; Genes; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hematopoietic System; Human; improved; In Vitro; in vitro Assay; in vivo; Individual; Infusion procedures; Injury; Ionizing radiation; Laboratories; Lung; Mammals; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Natural regeneration; novel strategies; Outcome; Pancytopenia; Paracrine Communication; Pathway interactions; Pattern; peripheral blood; prevent; progenitor; Radiation; Radiation Injuries; Radiation Syndromes; Radioprotection; Recovery; repaired; Replacement Therapy; Research; research study; response; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA Sequences; Role; Screening procedure; Series; Signal Pathway; Signal Transduction; stem; Stem cells; Syndrome; System; Target Populations; Therapeutic; Time; Tissues; Transplantation; Vascular Endothelial Cell; Vascular Endothelium
Relevance: Recovery of bone marrow function is the rate limiting step that determines survival after exposure to even modest doses of radiation. Strategies aimed at enhancing recovery of the hematopoietic system are of pivotal importance for improving the clinical outcomes for all individuals who have experienced significant radiation injury
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5U19AI091175-02_6789 (2011): $702406
THE ROLE OF CARBOXYPEPTIDASE B AND ITS SUBSTRATES IN RHEUMATOID ARTHRITIS
H William
Stanford Universitycity: Stanford country: United States (us)
Grant 5R01AI085268-02 from National Institute Of Allergy And Infectious Diseases
Abstract: Rheumatoid arthritis (RA) is the most common inflammatory joint disease of autoimmune etiology. Characteristic histologic features in RA joints are synovial hyperplasia, inflammatory cell infiltrates, bone erosions and fibrin deposits. Carboxypeptidase B (CPB) is well established to play an anti-fibrinolytic role by removing C-terminal lysine residues from fibrin, thereby preventing its cleavage by plasmin. Recently, C3a, C5a, thrombin-cleaved osteopontin (OPN-R) and bradykinin were identified as additional substrates of CPB. These substrates are involved in inflammatory pathways including chemotaxis and T cell activation. CPB removes arginine residues from the C-terminus of these substrates and is thereby postulated to modulate biologic function of these inflammatory mediators. We discovered that CPB deficient mice developed dramatically more severe arthritis as compared to wild type (WT) controls following transfer of anti-collagen antibodies. C5 deficient mice were also protected from arthritis, while bradykinin B2 receptor deficient mice developed arthritis equivalent in severity to that in WT mice. CPB deficient mice exhibited increased leukocyte chemotaxis in an acute peritonitis model, and in vitro chemotaxis assays showed that thrombin-cleaved OPN and C5a act as chemoattractants. Genetic association studies using tag single nuclear polymorphisms (SNPs) representing the CPB2 gene showed that the minor allele SNP rs1409433 was associated with a reduced RA disease susceptibility. The non- synonymous C1064T CPB SNP is in strong linkage disequilibrium with rs1409433, and the C1064T variant encoding CPB Thr325Ile has been reported to possess a longer half-life (Schneider et al, 2002). Our overriding hypothesis is that CPB plays a central role in down- regulating inflammatory responses in RA. We hypothesize that CPB cleaves C5a and OPN-R to inactivate their chemotactic properties, and thereby reduces inflammatory responses that contribute to the development and progression of RA. Finally, we hypothesize that individuals possessing the C1064T CPB variant express CPB Thr325Ile which possesses a longer half- life, and that long half-life CPB is associated with reduced incidence and severity of RA. This proposal is to investigate the role of CPB in RA Aim 1 will utilize murine models of RA to further characterize the mechanisms by which CPB modulates inflammatory arthritis; Aim 2 will determine if CPB cleavage of C5a and OPN-R inactivates their chemotactic properties; Aim 3 will investigate the genetic influence of CPB in human RA; and Aim 4 will characterize CPB protein expression in human RA. Rheumatoid arthritis (RA) is a chronic autoimmune arthritis that affects 0.6% of the world population. Current therapies are only partially effective, and there is great need for more effective therapeutic approaches. Success of the proposed experiments would demonstrate that CPB is a natural down-regulator of inflammation in RA. The proposed experiments will provide insights into pathogenesis, and could lead to development of new therapeutic approaches for RA
Keywords: Acute; Address; Affect; Alleles; Anti-inflammatory; Anti-Inflammatory Agents; Antibodies; Arginine; Arthritis; arthropathies; Autoantibodies; autoimmune arthritis; Autoimmune Process; BDKRB2 gene; Biological; Biological Assay; Biological Process; Bioluminescence; Blood Platelets; bone; Bradykinin; Bradykinin B2 Receptor; C-terminal; Carboxypeptidase B; Carboxypeptidase U; Cartilage; Cells; Characteristics; Chemotactic Factors; Chemotaxis; Chronic; Cleaved cell; Clinical; cohort; Collagen; Complement 3a; Data; Deposition; Development; Disease Progression; Disease susceptibility; Dose; Etiology; Exhibits; experience; Fibrin; Flow Cytometry; Genes; Genetic; genetic association; Genetic Polymorphism; Genotype; Half-Life; Hepatocyte; Histologic; Human; Hyperplasia; Immunoblotting; Immunohistochemistry; In Vitro; in vitro Model; in vivo; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; inflammatory marker; Inflammatory Response; insight; Joints; Knockout Mice; Laboratories; Lead; Letters; Leukocyte Chemotaxis; Linkage Disequilibrium; Liver; Lysine; Megakaryocytes; migration; Migration Assay; Minor; Modeling; Molecular Weight; Mus; Mutate; neutrophil; novel therapeutic intervention; Nuclear; osteopontin; Pathogenesis; Pathway interactions; Patients; Peritonitis; Plasmin; Play; Population; Predisposition; prevent; Property; protein expression; Proteins; public health relevance; Recombinants; Registries; Reporting; research study; Reverse Transcriptase Polymerase Chain Reaction; RGD (sequence); Rheumatoid Arthritis; Role; Sampling; Severities; success; Synovial Fluid; T-Cell Activation; Therapeutic; Thrombin; Tissue Sample; Tissues; Variant; Wild Type Mouse; Zymosan
Relevance: Rheumatoid arthritis (RA) is a chronic autoimmune arthritis that affects 0.6% of the world population. Current therapies are only partially effective, and there is great need for more effective therapeutic approaches. Success of the proposed experiments would demonstrate that CPB is a natural down-regulator of inflammation in RA. The proposed experiments will provide insights into pathogenesis, and could lead to development of new therapeutic approaches for RA
Project start date: 2010-08-01
Project end date: 2014-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01AI085268-02 (2011): $399135
TYROSINE KINASE PATHWAYS IN RHEUMATOID ARTHRITIS
H William
Palo Alto Institute For Res & Edu, Inc.city: Palo Alto country: United States (us)
Grant 5R01AR054822-06 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune arthritis, characterized by synovitis, pannus formation and periarticular erosions. The mechanisms underlying disease initiation and progression in RA remain poorly understood. Tyrosine kinases play a central role in the activation of signal transduction pathways and the cellular responses that mediate the pathogenesis of RA. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr-Abl expressing leukemias. We recently demonstrated that imatinib potently prevents and treats collagen-induced arthritis (CIA) in mice. We showed that micromolar concentrations of imatinib abrogated multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNFalpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFRbeta signaling and proliferation. This application is to further characterize the relative roles of these pathways in RA. Our overriding hypothesis is that one or more of these signal transduction pathways and its downstream cellular responses contribute to initiation and progression of autoimmune arthritis. To investigate this hypothesis, we will explore inhibition of PDGFR, c-Kit, c-Fms, and c-Abl by testing small molecule kinase inhibitors in the collagen-induced arthritis (CIA) model for RA. We will perform immunohistochemistry on joint tissue derived from mice with CIA and human RA patients to characterize the in situ expression, activation and cellular distribution of PDGFR, c-Kit, c-Fms and c-Abl. Finally, we will apply phospho-protein flow cytometry to characterize the activation states of kinases and signaling pathways in mast cells, fibroblast-like synoviocytes, synovial macrophage, and B cells derived from human RA and OA synovial tissue. Success of the proposed studies will advance our understanding of the mechanisms underlying the pathobiology of RA, and could lead to clinical trials of selective tyrosine kinase inhibitors in RA. Relevance to public health Rheumatoid arthritis (RA) is a chronic autoimmune arthritis that affects 0.6% of the world population. Current therapies are only partially effective, and there is great need for more effective therapeutic approaches. Tyrosine kinase inhibition represents a promising new therapeutic approach
Keywords: ABL1 gene; Affect; Antibodies; autoimmune arthritis; Autoimmune Process; Automobile Driving; B Cell Proliferation; B-Lymphocytes; base; Biological Assay; Blood; bone; c-abl Proto-Oncogenes; c-fms Proto-Oncogenes; Case Study; Cell Differentiation process; Cell Line; cell type; Chronic; Clinical; Clinical Trials; Collagen Arthritis; cytokine; Cytokine Activation; Disease; experience; Fibroblasts; Flow Cytometry; Gastrointestinal Stromal Tumors; Human; Imatinib; Imatinib mesylate; Immunoglobulins; Immunohistochemistry; In Situ; In Vitro; Inflammatory; inhibitor/antagonist; Inhibitory Concentration 50; insight; Interleukin-1; Interleukin-6; joint destruction; Joints; kinase inhibitor; Lead; leukemia; Ligands; macrophage; Macrophage Colony-Stimulating Factor; mast cell; Mediating; Methodology; Modeling; monocyte; Mononuclear; Mus; Myelogenous; novel therapeutic intervention; Osteoclasts; Pathogenesis; Pathway interactions; Patients; PDGFRB gene; Phospho-Specific Antibodies; Phosphorylation; Phosphotransferases; Platelet-Derived Growth Factor Receptor; Play; Population; prevent; Production; Property; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Protein c-kit; public health medicine (field); Receptor Protein-Tyrosine Kinases; Relative (related person); response; Rest; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; small molecule; Specificity; Staining method; Stains; Stimulus; success; Synovial Fluid; Synovial Membrane; Synovitis; Testing; Therapeutic; Tissues; TNF gene; TNFSF11 gene; Tyrosine Kinase Inhibitor
Project start date: 2007-06-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
5R01AR054822-06 (2011): $278833
H William, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Abstract: Research Base The MDCTR Research Base includes 69 investigators, 30 from the UM Department of Internal Medicine and 18 from other medical school departments including Pediatrics, Family Medicine, Medical Education, Ophthalmology, Obstetrics and Gynecology, Neurology, Physical Medicine and Rehabilitation, and Urology. Eight investigators come from the School of Public Health, 2 from the School of Social Work, 1 from the School of Nursing, 1 from the School of Dentistry, and 1 from the Institute for Social Research. In addition, 7 come from affiliated Universities and Research Institutes. Research Base investigators are united by their focus on developing, implementing, and evaluating evidence-based approaches to prevent and treat diabetes that can be disseminated and sustained in clinical and community settings outside of the traditional academic research setting. Interventions have been directed at patients, providers, practices, health systems, and communities. They have involved non-traditional study designs, novel measurements, and economic analyses; new intervention strategies, tools, and platforms; and a focus on health disparities, cultural competence, and community-based participatory research
Keywords: base; Clinical; community based participatory research; Community Health Systems; community setting; cultural competence; Diabetes Mellitus; Discipline of obstetrics; Economics; evidence base; Family Practice; Gynecology; health disparity; Institutes; Internal Medicine; Intervention; Measurement; Medical Education; medical schools; Michigan; Neurology; novel; Ophthalmology; Patients; Pediatrics; Physical Medicine; prevent; Provider; Public Health Schools; Rehabilitation therapy; Research; Research Design; Research Institute; Research Personnel; School Dentistry; School Nursing; Schools; social; Social work (field); tool; Translational Research; Universities; Urology
Budget start date: 6-SEP-2011
Budget end date: 30-AUG-2012
PFA/PA: RFA-DK-10-009
1P30DK092926-01_5555 (2011): $150048
H William, Senior Staff Investigator
Henry Ford Health Systemcity: Detroit country: United States (us)
Abstract: Renin is the rate-limiting enzymatic step in angiotensin II formation. cAMP stimulates renin release from juxtaglomerular (JG) cells. Calcium (Ca) is inhibitory, as increased extracellular Ca suppresses renin release, presumably by increasing intracellular Ca. We found that JG cells express Ca-sensing receptors (CaSR). Further, we found CaSR activation reduces basal cAMP production and renin release. Our data suggest CaSR activation increases intracellular Ca, suppressing the Ca-inhibitable isoform (V) of adenylyl cyclase in the JG cells, decreasing cAMP and inhibiting renin release. Conversely, decreased extracellular Ca should inactivate CaSR, increasing cAMP formation and thus stimulating renin release. In addition, cAMP is degraded by phosphodiesterases (PDE), and isoform PDE 1 is Ca dependent, suggesting CaSR activation exaggerates cAMP degradation, reducing renin release. We hypothesize that increased extracellular Ca activates CaSR on JG cells, thereby increasing intracellular Ca. This, in turn, reduces cAMP production by the Ca-inhibitable isoform adenylyl cyclase V and augments cAMP degradation by the Ca-dependent PDE 1, thereby reducing renin release. This hypothesis will be tested in 4 aims. Aim I. Hypothesis Activation of CaSR by physiological increases in extracellular Ca increases intracellular Ca and thus inhibits renin release. Aim II. Hypothesis Activation of CaSR inhibits renin release by activating L-type Ca channels and stimulating Ca release from intracellular stores. Aim III. Activation of CaSR inhibits adenylyl cyclase V and activates PDE 1, both resulting in decreased cAMP and inhibition of renin release. Aim IV. Hypothesis Increases in delivery of NaCI to the thick ascending limb will increase interstitial Ca in the renal cortex, activating CaSR on JG cells, which will in turn suppress renin. We will activate or inhibit JG cell CaSR in culture and study changes in intracellular Ca, Ca channels, cAMP synthesis and degradation, and renin release. In vivo, we will study acute and chronic changes in cortical interstitial Ca, CaSR activation or inhibition, cAMP formation and renin secretion. This project relates to the central theme because the renin- angiotensin system is a renal paracrine/autocrine system influencing renal perfusion, Na, Ca and blood pressure. The information from this project will be integrated with that from all other projects. It will use all of the cores. Our findings may lead to new treatments of hypertension from new insights into mechanisms that regulate renin
Keywords: Acute; Adenylate Cyclase; Agonist; Angiotensin II; autocrine; Blood Pressure; blood pressure regulation; Calcium; Calcium Channel; Calcium-Sensing Receptors; Cells; Chronic; Coupling; Cyclic AMP; Data; Dominant-Negative Mutation; Equilibrium; extracellular; Fluorescence; Furosemide; hypertension treatment; In Vitro; in vivo; inhibitor/antagonist; insight; interstitial; Juxtaglomerular Cell; Kidney; kidney cortex; L-Type Calcium Channels; Lead; Limb structure; Measures; Mediating; novel; paracrine; Perfusion; phosphodiesterase V; phosphoric diester hydrolase; Physiological; Preparation; prevent; Production; Protein Isoforms; receptor; Receptor Activation; Renin; Renin-Angiotensin System; response; Role; sensor; Sodium; Testing; Thick; Transference (Psychology)
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5P01HL090550-03_5161 (2011): $374690
MAGNESIUM INDUCED DEVELOPMENTAL NEUROAPOPTOSIS
H William
Washington Universitycity: Saint Louis country: United States (us)
Grant 5K08NS048113-05 from National Institute Of Neurological Disorders And Stroke
Abstract: Recent studies have demonstrated widespread apoptotic neurodegeneration induced in the developing rodent brain by transient exposure to various agents that suppress neuronal activity, including NMDA glutamate antagonists, GABAA agonists, ethanol, and sodium channel blockers. The potential neurotoxic effects of MgSO4 have important public health implications due to its frequent use in obstetrics for preterm labor and pre-eclampsia/eclampsia resulting in fetal exposure during the synaptogenic period. Although Mg++ has been used in obstetrics for over 60 years, there is a lack of studies addressing the effects of increased Mg++ on the fetal brain. Mg++ has inhibitory properties at numerous cellular membrane receptors and ion channels, and can enhance surface charge screening effects. I have developed preliminary in vivo evidence that exposure to Mg++ can trigger apoptotic neurodegeneration in the developing rodent brain. In order to expand upon these in vivo findings, I have performed experiments exposing cultured hippocampal neurons to Mg++ and found similar neurodegenerative effects. I hypothesize that because of its intrinsic neuroinhibitory properties, Mg++ at non-physiologically high concentrations can suppress neuronal activity to a degree that is sufficient to precipitate neuroapoptosis. The Aims of the proposed research are 1) to further characterize the neurodegenerative reaction induced in the developing mouse brain by Mg++ with respect to nature, pattern, pattern, time-course and age specificity; 2) determine dose-response parameters in vitro and in vivo, including lowest effective dose, and compare this with doses to which the developing human brain is sometimes exposed; 3) investigate mechanisms(s) and protective strategies in both in vitro and in vivo models. In the course of this work I will learn various histological methods, including electron microscopy and immunohistochemistry; stereologic techniques to quantitate neuronal injury; western blotting for evaluating biochemical pathways; transgenic animals, electrophysiology, and Ca++ and Mg++ imaging to aid in mechanistic studies; and pharmacological interventions to evaluate protective strategies. In addition, I will develop an understanding of neuroanatomy, neurochemistry, toxicokinetics and toxicodynamics, and statistical methods. My preceptors, Dr. John Olney, Dr. Eugene Johnson and Dr. Steve Mennerick, will provide close guidance and supervision during the proposed research period
Keywords: 5-Oxazolecarboxylic acid, 2-(6-(bis(carboxymethyl)amino)-5-(2-(2-(bis(carboxymethyl)amino)-5-methylphenoxy)ethoxy)-2-benzofuranyl)-; Absolute ethanol; Address; Age; Agonist; Alcohol, Ethyl; Ammon Horn; Anesthestic Drugs; Anesthetic Agents; Anesthetic Drugs; Anesthetics; Animals; Anticonvulsant Agent; Anticonvulsant Drugs; Anticonvulsants; Anticonvulsive Agents; Anticonvulsive Drugs; Apopain; Apoptosis; Apoptosis Pathway; Apoptotic; BAX; BAX gene; BCL2-Associated X Protein Gene; BCL2L4; Biochemical Pathway; Blotting, Western; Brain; Calcium Channel; Calcium Channel Antagonist Receptor; CAP4 protease; CASP-3; CASP3; CASP8 Protein; caspase; Caspase 3, Apoptosis-Related Cysteine Protease; Caspase Inhibitor; caspase-3; caspase-8; Caspase-8/Flice; Cell Culture Techniques; Cell Death; Cell Death, Programmed; Cell Survival; Cell Viability; Cell-Death Protease; Cell/Tissue, Immunohistochemistry; Cells; Cellular Membrane; Cessation of life; Charge; Childhood; Clinical; Common Rat Strains; Cornu Ammonis; CPP-32; CPP32; CPP32 protein; CPP32B; CPP32beta; Culture Media; cystein protease; cystein proteinase; cysteine endopeptidase; Cysteine Protease CPP32; cysteine protease P32; Death; Development; Discipline of obstetrics; Divalent Cations; Dose; Drug usage; drug use; EAA Antagonists; Eclampsia; Electron Microscopy; Electrophysiology; Electrophysiology (science); Encephalon; Encephalons; Ethanol; ETOH; Excitatory Amino Acid Antagonists; experiment; experimental research; experimental study; Exposure to; FADD-homologous ICE/CED3-Like Protease; FADD-Like ICE; fetal; fetal exposure; Fetus; FLICE protein; Fluorescent Probes; Foundations; Fura-2; gene product; Genes; Gestation; Gestosis, EPH; Glutamate Antagonists; Glutamate Receptor Antagonists; Grain Alcohol; growth media; hippocampal; Hippocampus; Hippocampus (Brain); Histological Technics; Histological Techniques; Human; Human, General; ICE-like protease; IHC; Image; imaging; Immunohistochemistry; Immunohistochemistry Staining Method; in utero exposure; In Vitro; in vivo; in vivo Model; inhibitor; inhibitor/antagonist; Intervention; Intervention Strategies; interventional strategy; intra-uterine environmental exposure; intrauterine environmental exposure; Investigators; Ion Channel; Ion Channels, Calcium; Ionic Channels; Knockout Mice; Labor, Premature; Learning; MACH protein; magfura-2; Magnesium; Mammals, Mice; Mammals, Rats; Mammals, Rodents; Man (Taxonomy); Man, Modern; Mch5 protease; Mediating; Medicine; Membrane; Membrane Channels; membrane structure; Metabolic Networks; Methods; Methods and Techniques; Methods, Other; Methylcarbinol; Mg element; Mice; Mice, Knock-out; Mice, Knockout; Murine; Mus; N methyl D aspartate; N Methyl D aspartic Acid; N-Methyl-D-aspartate; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; necrocytosis; Nerve Cells; Nerve Degeneration; Nerve Unit; Nervous System, Brain; Neural Cell; neural degeneration; Neuranatomies; Neuranatomy; Neuroanatomies; Neuroanatomy; neurochemistry; Neurochemistry; Neurocyte; neurodegeneration; Neuron Degeneration; neuron injury; neuron toxicity; neuronal; neuronal degeneration; Neuronal Injury; neuronal toxicity; Neurons; Neurophysiology / Electrophysiology; neuroprotection; neurotoxic; neurotoxicity; neurotrophic factor; neurotrophin; neutrophin; NMDA; NMDA Receptor-Ionophore Complex; NMDA Receptors; Null Mouse; Obstetrics; PARP Cleavage Protease; pathway; Pathway interactions; Pattern; pediatric; Perinatal Exposure; Pre-Eclampsia; Preeclampsia; Pregnancy; pregnancy toxemia/hypertension; Premature Labor; Premature Obstetric Labor; Preterm Labor; prevent; preventing; Process; programs; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; protein blotting; Proteins; Proteinuria-Edema-Hypertension Gestosis; Public Health; public health medicine (field); Rat; Rattus; Reaction; receptor; Receptor Protein; Receptors, Calcium Channel Blocker; Receptors, N-Methylaspartate; Research; Research Personnel; research study; Researchers; response; Rodent; Rodentia; Rodentias; SCA-1; Science of Medicine; Science of neurochemistry; screening; Screening procedure; screenings; sedative; Series; Sodium Channel Blockers; Specificity; SREBP Cleavage Activity 1; Statistical Methods; Supervision; Surface; synapse formation; synaptogenesis; Technics, Histologic; Techniques; Techniques, Histologic; Testing; Time; Toxemias, Pregnancy; Toxicokinetics; Transgenic Animals; VDCC; Voltage-Dependent Calcium Channels; Western Blotting; Western Blottings; Western Immunoblotting; Wild Type Mouse; Work; Yama; Yama protein
Project start date: 2006-01-01
Project end date: 2012-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-00-003
5K08NS048113-05 (2011): $161901
FUNCTIONAL INTERACTIONS BETWEEN HEMATOPOIETIC PROGENITORS AND ENOTHELIUM
H William, Professor
Oregon Health And Science Universitycity: Portland country: United States (us)
Grant 5R01HL069133-08 from National Heart, Lung, And Blood Institute
Abstract: Recent studies from our laboratory indicate that the close functional relationship between hematopoiesis and the vascular system first identified in early embryonic development extends into adult life. A single adult hematopoietic stem cell can differentiate into endothelial cells and blood cells, demonstrating the existence of adult cells with hemangioblast activity. Although bone marrow- derived hematopoietic stem cells (HSCs) and their progeny are thought to contribute to angiogenesis, relatively little is known about the identity of the progenitor cells involved and the mechanisms by which they contribute to blood vessel repair. We now hypothesize that the differentiation of HSCs into mature endothelial cells and the production of pro-angiogenic cytokines by HSCs and/or their progeny are critical factors regulating vascular endothelial homeostasis. To test this hypothesis, we propose to 1) determine the contribution of hematopoietic progenitors to the endothelial cell compartment during normal development; 2) evaluate the phenotype and functional activity of circulating pro-angiogenic hematopoietic cells; 3) determine the functional role of bone marrow derived endothelial cell progenitors during tissue regeneration. This research is significant as it is designed to identify novel cellular mechanisms responsible for vascular and hematopoietic system regeneration. PUBLIC HEALTH RELEVANCE The purpose of these studies is to enhance our knowledge of the close functional relationship between blood cell development and the vascular system. The results of this research have important implications for our understanding of disorders of the bone marrow and the vascular system. Ultimately this will lead to the identification of potential therapeutic targets for a number of diseases including leukemia, coronary artery disease and peripheral vascular disease
Keywords: Address; Adult; angiogenesis; base; Biological Assay; Blood Cells; Blood Circulation; Blood Vessels; Bone Marrow; Bone Marrow Diseases; Cell surface; Cells; Coronary Arteriosclerosis; cytokine; density; design; Development; Disease; Embryonic Development; Endothelial Cells; Endothelium; Fetal Liver; Goals; Health; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hematopoietic System; Homeostasis; In Vitro; in vivo; injured; interest; Investigation; Knowledge; Laboratories; Lead; leukemia; Life; Liver Regeneration; Maintenance; Natural regeneration; novel; Parabiosis; peripheral blood; Peripheral Vascular Diseases; Phenotype; Population; precursor cell; Pregnancy; Production; progenitor; repaired; Research; Role; Stem cell transplant; Stem cells; Testing; therapeutic target; tissue regeneration; Tissues; Vascular Endothelium; Vascular System
Project start date: 2001-09-30
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01HL069133-08 (2011): $315000
SUSTAINED RELEASE INNER EAR DELIVERY OF CORTICOSTEROID
H William
O-ray Pharma, Inc.city: Pasadena country: United States (us)
Grant 5R44DC008477-03 from National Institute On Deafness And Other Communication Disorders
Abstract: Project Summary The broad long term goal of this research program is to reduce or eliminate deafness by developing sustained release intracochlear drug delivery systems. The goal of this project is to develop a steroid eluting cochlear implant. Currently, cochlear implantation leads to loss of residual hearing and the procedure is therefore reserved for the profoundly deaf. Inflammatory events at insertion are thought to contribute to this loss, and intracochlear steroids have demonstrated the potential to reduce inflammation and preserve residual hearing. The potential for implanting cochlear devices into people with residual hearing expands the world market to 278 million people suffering from moderate to profound hearing loss. In Phase 1 we formulated sustained release delivery systems for fluticasone, tested in vitro release, and confirmed sustained release and safety in an animal model. We furthermore formulated prototype cochlear implants releasing fluticasone, and have laid the basis for further commercialization with a corporate partner Cochlear Corporation, the market leader in the field. In this Phase 2 work we propose to develop an inner ear delivery system for the steroid fluticasone to be used in cochlear implantation, and to test this formulation in an animal model of insertion trauma. The specific aims of this proposal are to 1, manufacture steroid eluting cochlear implants; 2, confirm the in vitro release characteristics of these implants; and 3, test the in vivo efficacy of these implants after insertion into the inner ear of the guinea pig in a trauma insertion model. We have an understanding with Cochlear Corporation when we demonstrate efficacy in an animal model they will license our technology. They have committed the donation of implants and technical expertise in the manufacturing of their system to this project. The team of investigators is expert in polymer chemistry, pharmacokinetics, drug development intracochlear pharmacokinetics and clinical otolaryngology. We have experience in all aspects of the drug development process, from concept to approval and marketing. Cochlear implants are medical devices that electrically stimulate the auditory nerve fibers of the inner ear of patients who are profoundly deaf giving them a sensation of sound. Historically, cochlear implants were used for patients who had no hearing within the ear. Cochlear implants that elute steroids have the potential to reduce the loss of hearing from the traumatic insertion of the implant. This greatly expands the number of people who could benefit from obtaining a cochlear implant from those with profound hearing loss to those with moderate hearing loss. We have the technology and the expertise to develop steroid eluting cochlear implants
Keywords: Acoustic Nerve; Adrenal Cortex Hormones; Animal Model; base; Blindness; Businesses; Cavia; Characteristics; Clinical; Clinical Research; Cochlear implant procedure; Cochlear Implants; commercialization; Commit; Cytomegalovirus Retinitis; Deafness; Development; Devices; Diabetic Retinopathy; Drug Delivery Systems; drug development; Drug Formulations; Drug Kinetics; Ear structure; Electrodes; Esthesia; Event; experience; fluticasone; Fluticasone propionate; Future; Goals; Grant; Hearing; Hearing Impaired Persons; hearing impairment; Implant; In Vitro; in vitro testing; in vivo; Inflammation; Inflammatory; inner ear diseases; innovation; Knowledge; Labyrinth; Letters; Licensing; Macular degeneration; Marketing; Medical Device; Methodology; Modeling; Nerve Fibers; novel; Otolaryngology; particle; Patients; Pharmaceutical Preparations; Phase; Polymer Chemistry; Presbycusis; Procedures; Process; product development; Production; programs; prototype; public health relevance; Research; Research Personnel; Residual state; Safety; sound; Steroids; System; Technical Expertise; Technology; Testing; Time; Trauma; Work
Relevance: Cochlear implants are medical devices that electrically stimulate the auditory nerve fibers of the inner ear of patients who are profoundly deaf giving them a sensation of sound. Historically, cochlear implants were used for patients who had no hearing within the ear. Cochlear implants that elute steroids have the potential to reduce the loss of hearing from the traumatic insertion of the implant. This greatly expands the number of people who could benefit from obtaining a cochlear implant from those with profound hearing loss to those with moderate hearing loss. We have the technology and the expertise to develop steroid eluting cochlear implants
Project start date: 2006-01-01
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-09-080
5R44DC008477-03 (2011): $535685
WOMEN´S HIV RISK: ALCOHOL INTOXICATION, VICTIMIZATION HISTORY & PARTNER FACTORS
H William, Professor
University Of Washingtoncity: Seattle country: United States (us)
Grant 5R01AA016281-05 from National Institute On Alcohol Abuse And Alcoholism
Abstract: Project Summary HIV infection is currently the 6th leading cause of death among American women aged 25-34 years, and heterosexual contact accounts for 80% of HIV infections in women. Highly controlled laboratory experiments have indicated that alcohol intoxication fosters HIV-related risk behaviors; this may be particularly true among women with a history of child sexual abuse (CSA) or later sexual assault (SA), who it is estimated comprise over 20% of all women. Research has also shown CSA-positive (CSA+) and SA-positive (SA+) women are at higher risk of HIV infection than those without such a history. This heightened risk may in part be related to alcohol use. Because the bulk of the extant research has been descriptive and correlational, virtually nothing is known about how alcohol and contextual factors such as partner characteristics operate in-the-moment to affect sexual decision-making (SDM) processes of CSA+/SA+ women, potentially increasing their risk of contracting HIV. The present project addresses this knowledge gap. Two large scale alcohol administration experiments will examine risky SDM processes among female social drinkers, aged 21-30, with and without victimization histories, in an experimental dating analogue. Drawing on existing theory, one type of partner characteristic will be manipulated in each experiment a recent partner´s relationship potential (low v. high); and an ongoing partner´s pressure to have unprotected intercourse (low pressure vs. high pressure). Alcohol myopia theory will be employed as a potentially useful theoretical framework. Possible mediators of the risky SDM-alcohol connection that will be investigated in-the-moment include risk perception, self-efficacy, and anticipated partner reaction to condom negotiation. Potential moderating influences of background characteristics will also be explored, including alcohol expectancies and drinking habits, sensation seeking, traumatic sexualization, condom attitudes and sexual experiences, as well as prior victimization factors, such as type, age, and severity. Relevance The proposed studies will advance our understanding of in-the-moment dynamics of risky HIV-related decision-making and behavior in intoxicated and sober binge-drinking women who have and have not been sexually victimized. Findings will greatly inform designers of prevention programs, who remain frustrated in their efforts to stem the spread of HIV in women and eager to learn of new and promising targets for intervention. The information gleaned from the proposed studies could be used to design HIV prevention programs that work for social-drinking women, particularly those with a history of victimization, a substantial but underserved population
Keywords: 21 year old; Accounting; Acute; Address; Adolescence; Adult; Affect; Affective; African; African American; Age; aged; AIDS diagnosis; AIDS prevention; Alcohol consumption; alcohol effect; alcohol expectancy; Alcohol or Other Drugs use; Alcoholic Intoxication; Alcohols; American; analog; Attitude; Behavior; binge drinking; Cause of Death; Characteristics; Child Sexual Abuse; Childhood; Cognitive; condoms; Consumption; contextual factors; Contracts; Decision Making; design; Distal; dosage; drinking; Drug usage; Esthesia; experience; Female; Fostering; Fright; Glean; Habits; Heterosexuals; high risk; high risk sexual behavior; High Risk Woman; HIV; HIV Infections; in vivo; Individual; Infection; Intervention; Intoxication; Knowledge; Laboratories; Learning; Link; Measures; Mediating; Mediation; Mediator of activation protein; men; Mental Health; Modeling; Myopia; Only Child; Patient Self-Report; Population; pressure; Prevention; Prevention program; Process; Reaction; Recording of previous events; Research; research study; response; revictimization; Risk; Risk Behaviors; Risk Factors; risk perception; Risk-Taking; Role; Sampling; Science; Self Efficacy; Severities; sex; Sex Behavior; sex risk; Sexual abuse; sexual assault; sexual coercion; sexual encounter; Sexual Transmission; Sexuality; sobriety; social; Social work (field); Solid; stem; Substance abuse problem; success; theories; Underserved Population; United States National Institutes of Health; Unsafe Sex; Victimization; Woman
Project start date: 2007-09-27
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-07-028
5R01AA016281-05 (2011): $449929
Sponsored Links Excellgen http://Excellgen.com
VASCULAR SURGERY SCIENTIST TRAINING PROGRAM
H William, Professor
Northwestern Universitycity: Chicago country: United States (us)
Grant 5T32HL094293-03 from National Heart, Lung, And Blood Institute
Abstract: Peripheral arterial disease (PAD) is an underdiagnosed manifestation of systemic atherosclerosis and is associated with significant clinical mortality and complications such as stroke, lower extremity amputation, and death, it is critical to gain new understandings of the disease process from different clinical perspectives to design and implement new treatment strategies and means of disease prevention. Vascular surgeons are at the interface between patient care and fundamental and translational research. Translational research is a multidimensional process in which there is a dynamic communication between the clinician and the basic scientist. At Northwestern University Feinberg School of Medicine, we have the ideal environment to train the next generation of vascular clinician-scientist. The primary goal of this training grant is to increase the number of clinician-scientists interested in vascular disease. This two-year program will be the foundation for these trainees to gain the requisite research experience to later apply for K08/K23 mentored funding. This is a mentored research training experience for residents in general surgery and vascular surgery within a seamless multidisciplinary research environment. The key to this mentored research training program is the development of the individualized training plan by the mentor and trainee. The mentor and the trainee will decide on a research training program, perform a needs assessment, and set specific goals and objectives. Then specific instructional methods and materials will be developed by the mentor. The trainee will then work alongside the mentor in the lab or office, depending upon the trainee´s area of interest. Trainees may select one of several tracks or a combination of tracks that meets their ultimate research objectives and interests, including (1) vascular biology with a basic science emphasis, (2) clinical research including outcome studies, (3) biomedical devices in partnership with the Department of Biomedical Engineering, or (4) an integrated program designed by the trainee and his/her mentors. The strength of this program lies in its breadth and flexibility. Our goal is to match the research interest of the trainee to mentors, coursework, seminars, meetings, and a research plan that will collectively provide the experience necessary to launch a successful career as a physician scientist
Keywords: Blood Vessels; Operative Surgical Procedures; Scientist; Training Programs
Project start date: 2009-05-01
Project end date: 2014-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-08-226
5T32HL094293-03 (2011): $261293
H William, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Abstract: Overview The Michigan Center for Diabetes Translational Research (MCDTR) Enrichment Program is designed to advance type 2 translational research in diabetes, promote scientific exchange among investigators, and enhance interactions among trainees, diabetes researchers, and investigators from other fields locally, regionally, nationally, and internationally. The Michigan Diabetes Research and Training Center (MDRTC) historically engaged in teaching and provided research experience to undergraduate and graduate students, medical students, fellows, and postdoctoral fellows; developed seminars and workshops; invited visiting professors and guest speakers; and identified extramural and intramural researchers to present at weekly seminars. The MDRTC also applied for and received funding from external agencies to support visiting professors. The MDRTC Administration Core personnel are experienced in implementing an Enrichment Program and will employ their experience to develop similar programs for the MCDTR. The MCDTR will partner with the Michigan Clinical and Translational Science Award (CTSA), the Michigan Comprehensive Diabetes Center, the Michigan Nutrition and Obesity Research Center, the Geriatrics Research, Education and Clinical Center, the Urban Research Center, the Center for Managing Chronic Diseases, and the Veterans Affairs Ann Arbor Healthcare System´s Health Services Research and Development Service (HSR&D) among others to provide seminars in diabetes translational research, symposia, and workshops. The MCDTR will also partner with the Michigan Institute for Clinical and Health Research, the K30 Training Grant in Clinical Research Design and Statistical Analysis, and the Robert Wood Johnson Clinical Scholars Program to promote their education and mentoring programs. William H. Herman, M.D., M.P.H. Center Director, will lead the Enrichment Program for the Center and will interact with the leads of the programs outlined above
Keywords: Address; Adult; African American; Allied Health Personnel; American; American Medical Association; Applications Grants; Area; Attitude; Award; base; Basic Science; Behavior; Bioethics; Biometry; Blood Vessels; California; Caring; Centers for Disease Control and Prevention (U.S.); Chicago; Child; Childhood; Chin; Chronic; Chronic Disease; Clinic; Clinical; clinical care; clinical conference; clinical decision-making; clinical epidemiology; Clinical Medicine; Clinical Research; Clinical Sciences; Clinical Services; Clinical Trials; Collaborations; college; Commit; Communication; Communities; Consultations; continuing medical education; Cultural Diversity; design; diabetes education; Diabetes Mellitus; Diet Habits; Dietary Intervention; Dietetics; Discipline; Discipline of Nursing; Discipline of obstetrics; disorder prevention; Doctor of Medicine; Doctor of Philosophy; Doctor of Public Health; Educational aspects; Educational Curriculum; Educational process of instructing; Educational workshop; Endocrine; Endocrinology; Enrollment; Epidemiologic Studies; Epidemiology; Ethnicity aspects; Evaluation; experience; Extramural Activities; Faculty; Family; Family Practice; Fellowship; Fellowship Program; Fostering; Foundations; Funding; Future; Generations; Geriatrics; Goals; graduate medical education; graduate student; Grant; Grant Review; Gynecology; Health; health administration; health care delivery; health care quality; Health Occupations; Health Policy; Health Professional; Health Services Research; Health system; Healthcare Systems; Home visitation; Hospitals; House Call; Household; Human Resources; Individual; innovation; Inpatients; Institutes; Institutional National Research Service Award; instructor; Insulin; interest; Internal Medicine; Joint Commission on Accreditation of Healthcare Organizations; Journals; Laboratories; Lead; Leadership; lectures; Letters; Life; Life Style; Marshal; Master of Public Health; Master of Science; Measurement; Medical; Medical Education; Medical History; medical schools; Medical Students; Medicine; meetings; member; Mentors; Michigan; Mortality Vital Statistics; National Committee for Quality Assurance; National Institute of Diabetes and Digestive and Kidney Diseases; NCI Scholars Program; Non-Insulin-Dependent Diabetes Mellitus; Nursing Students; nutrition; Obesity; Occupations; Operative Surgical Procedures; Outcome; Outpatients; Patients; Pediatrics; peer; Pharmacy facility; Pharmacy Students; Physicians; Play; Policy Research; Postdoctoral Fellow; Prevention; Primary Care Physician; Principal Investigator; professor; programs; public health medicine (field); public health research; Public Health Schools; Quality of Care; Quality of life; racial and ethnic; Recruitment Activity; Research; research and development; Research Design; Research Personnel; Research Project Grants; research study; Research Training; Residencies; Risk; Rods (Retina); Role; Schedule; Scholarship; School Nursing; Schools; Science; Scientist; sedentary; Self Management; Series; Services; Site; skills; Societies; Socioeconomic Status; sociologist; Spirituality; Students; symposium; teacher; theories; Time; Training; Training Programs; Translational Research; United States National Institutes of Health; Universities; Update; Veterans; Visit; volunteer; Wood material; Work
Budget start date: 6-SEP-2011
Budget end date: 30-AUG-2012
PFA/PA: RFA-DK-10-009
1P30DK092926-01_5557 (2011): $87696
PILOT AND FEASIBILITY STUDY GRANTS PROGRAM
H William, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Abstract: Overview For the past 33 years, the Michigan Diabetes Research and Training Center (MDRTC) Pilot/Feasibility Study (P/FS) Grants Program has attracted young investigators to diabetes-related research and has stimulated new biomedical, behavioral, clinical, epidemiologic, translational, and health services research. On rare occasions, P/FS grants have also encouraged established investigators in other disease areas to focus their expertise on problems related to diabetes, and established investigators in diabetes to explore new, high-risk directions. Major benefits of the P/FS Grants Program are that it has attracted new investigators into research careers in diabetes and related disorders, has attracted investigators from Schools and Institutes across the University of Michigan (UM) to participate in the MDRTC, and has made the MDRTC a catalyst for new interdisciplinary collaborations. With establishment of the Michigan Center for Diabetes Translational Research (MCDTR), we propose to expand the P/FS Grants Program to type 2 translational researchers who are center members across the region and nation, to further stimulate new investigators to enter the field and to foster productive collaborations. The ultimate goal of the P/FS grants program is to enable awardees to generate sufficient bodies of preliminary data to successfully apply for major research funding from the NIH or other national granting agencies and to accelerate the pace of translation of proven-effective interventions into real world health care settings, communities, and populations at risk. Each year, $50,000 in NIH funds awarded to the MCDTR will be devoted to funding at least two P/FS grants. NIH funds may be supplemented with institutional funds (see below). Management The Administration Core of the MCDTR will oversee the P/FS Grants Program. In order to optimize the use of NIH funds, the MCDTR and the MDRTC will share responsibility for the administration of the P/FS Grants Program. William H. Herman, M.D., M.P.H. and Martin G. Myers, Jr., M.D., Ph.D. will co-direct the program. Together they will solicit applications and requests for extramural peer review, assign internal reviewers, convene the meeting of the P/FS Grants Program Advisory Council, notify awardees, and track outcomes including subsequent extramural grant awards and publications. After the award, the Administration Core will also ensure distribution of funds to awardees, monitor expenditures, and obtain annual status reports on funded projects. Dr. Herman provides scientific oversight for the identification of external reviewers for T1 and T2 translational research applications and Dr. Myers provides oversight for the biomedical research applications. Currently, the Grants Program Advisory Council includes 7 translational researchers and 7 biomedical researchers (Table 1). In the future, a minimum of one-third of Council members will be experts in type 2 translational research in diabetes
Keywords: Area; Award; Behavioral; Biomedical Research; career; catalyst; Clinical; Collaborations; community setting; Data; Diabetes Mellitus; Disease; Doctor of Medicine; Doctor of Philosophy; effective intervention; Ensure; Epidemiology; Expenditure; Extramural Activities; Feasibility Studies; Fostering; Funding; Future; Goals; Grant; Health Services Research; Healthcare; high risk; Institutes; interdisciplinary collaboration; Master of Public Health; meetings; member; Michigan; Monitor; Outcome; Peer Review; Pilot Projects; Populations at Risk; programs; Publications; Reporting; Request for Applications; Research; Research Personnel; Research Training; Schools; Translational Research; Translations; United States National Institutes of Health; Universities; World Health
Budget start date: 6-SEP-2011
Budget end date: 30-AUG-2012
PFA/PA: RFA-DK-10-009
1P30DK092926-01_5556 (2011): $116039
H William
Johns Hopkins Universitycity: Baltimore country: United States (us)
Abstract: Over the past decade, knowledge about the pathogenesis of human tumors has been attributed to and limited by the availability of well-characterized human tissues and fluids. With this in mind, tissue/biologic fluid facilities have emerged as a means of overseeing specimen collection, storage, processing and distribution for investigative studies. The purpose of the Specimen Resource is to provide human tissues, biologic fluids and expert pathologic interpretation to SPORE investigators; and to maintain a large and diverse specimen bank for future studies. The Specimen Resource will collect tissues/biologic fluids in a manner that meets the needs of the individual investigators without compromising clinical patient care; store these samples in such a way as to ensure long-term security and easy accessibility; process samples so that they are suitable for further analysis; and distribute samples to investigators in a timely fashion. To maximize translational impact of the projects, specimens are collected and processed under the supervision of pathologists in close collaboration with a multidisciplinary team of clinical specialists and basic research investigators with a common expertise in neoplasia of the upper respiratory tract. A concerted effort to collect and bank tissue specimens and biologic fluids from the upper respiratory tract has been an ongoing effort since 1990. These materials have been collected with appropriate IRB approval and patient consent. The specimens are primarily obtained from patients with head and neck squamous cell carcinoma or from patients at risk of developing this tumor. The fresh frozen specimen bank currently houses 26,092 specimens from 5,147 patients including 3,381 carcinomas,4,838 phenotypically normal tissues including mucosa taken from the surgical margins of cancer resections,4,691 oral rinses/swabs, 3,831 plasma samples, 5,352 serum samples, and 166fine needle aspirates. These samples are cataloged in a state of the art database (i.e. HAND database) and efficiently stored for efficient retrieval. In many cases, the samples have already been processed (e.g.microdissected for enrichment of tumor DMA) and are available in the form of extracted DMA, RNA and/or protein. The Specimen Resource is staffed by pathologists with expertise in neoplasia of the upper respiratory tract, and has ready access to a laser capture microdissection facility, a tissue array facility, an immunohistochemistry facility, and an in-situ hybridization facility
Keywords: Aspirate substance; Basic Science; Carcinoma; Cataloging; Catalogs; Clinical; Collaborations; Consent; Databases; Ensure; Excision; Freezing; Future; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Housing; Human; human tissue; Immunohistochemistry; In Situ Hybridization; Individual; Institutional Review Boards; Knowledge; laser capture microdissection; Liquid substance; Malignant Neoplasms; meetings; Mind; Mucous Membrane; multidisciplinary; Needles; Neoplasms; Normal tissue morphology; Oral; Pathogenesis; Pathologic; Pathologist; Patient Care; Patients; Plasma; Process; Proteins; Reproduction spores; Research Personnel; Resources; Retrieval; Risk; RNA; sample collection; Sampling; Security; Serum; Specialist; Specimen; Supervision; Surgical margins; Swab; Tissue Banking; Tissue Banks; Tissue Microarray; Tissues; tumor; Upper respiratory tract
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5P50DE019032-10_9002 (2011): $176148
THE PARTNERSHIP FOR NATIVE AMERICAN CANCER PREVENTION (1 OF 2)
H William, Vice President For Research
Northern Arizona Universitycity: Flagstaff country: United States (us)
Grant 5U54CA143925-03 from National Cancer Institute
Abstract: Nitric oxide (NO) is a small, reactive molecule involved in numerous signaling pathways, including those regulating angiogenesis and metastasis. The primary cellular receptor for NO is soluble Guanylyl Cyclase (sGC), a heterodimeric hemoprotein of 150 kDa and an attractive target for the treatment of disease, including cancer. Binding of NO stimulates sGC activity, leading to the establishment of a cGMP signaling cascade. sGC is allosterically regulated by a variety of molecules, including NO, ATP, YC-1 (a small nucleotide-like pharmacophore), and by posttranslational modifications. Despite extensive study, little is known about the overall shape of sGC, the means by which allosteric regulation takes place, the arrangement of functional domains in the protein or the arrangement of the protein in the cell. We intend to fill this gap through fluorescence-based approaches that will allow us to measure structural changes within sGC, and also to monitor sGC localization within the cell. Specifically, we intend to incorporate paired fluorophores to full-length and truncated forms of sGC such that FRET measurements will reveal the distances between functional domains under stimulating and inhibiting conditions. We have developed a robust model system involving sGC from the hawk moth {Manduca sexta) with which to begin these studies, but will also include human sGC once the fluorescence system is established. We will investigate sGC conformational states not only with isolated material, but also in live cells. Additionally, we will use a combination of immunohistology and fluorescence microscopy to monitor localization of sGC under activating and inhibiting conditions. We have shown that sGC displays a punctuate arrangement in the cell, but the functional consequences of this stark pattern are unknown. Together, we expect that these studies will uncover the structural transitions that sGC undergoes and provide the framework for novel strategies in drug discovery. The generated results from this pilot project will provide the basis for future collaborative funding and research efforts
Relevance: The Partnership for Native American Cancer Prevention is collaboration between Northern Arizona University and the Arizona Cancer Center. Its mission is to alleviate the unequal burden of cancer among Native Americans of the Southwest through research, training and outreach programs that are collaborative with the communities they serve
Project start date: 2009-09-29
Project end date: 2014-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-CA-09-501
5U54CA143925-03 (2011): $1365386
CANCER PREVENTION & CONTROL: MULTIDISCIPLINARY TRAINING
H William, Professor
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 5R25CA081137-12 from National Cancer Institute
Abstract: More than 1.4 million new cancer cases are expected in 2009. Despite continuing improvements in treatment and prolonged survival, more than half a million Americans will die from cancer this year. Indeed, cancer accounts for one quarter of all deaths in the United States. Because lifestyle and environmental influences account for a substantial portion of the cancer burden, the importance of efforts in cancer prevention and control is increasingly recognized. In fact, the National Cancer Institute has noted the critical need to develop a cadre of highly trained research scientists with the necessary interdisciplinary skills to effectively and efficiently address behavioral factors in cancer prevention and control. The achievements of our graduates over the past decade reflect the success and the overall high quality of our training program in meeting NCI training goals. The successes of our past fellows include 1) publishing at least two peer-reviewed research reports while in our program; 2) obtaining full-time cancer prevention and control research positions at academic institutions (67% had done so); 3) holding senior level academic positions with multiple R-01 grants (five graduates from the first funding cycle -now out of the program more than 5 years); 4) receiving NCI career awards (seven of our graduates); and 5) 100% of our minority graduates now hold faculty appointments at academic institutions where they are engaged in cancer prevention and control research. The goal of the proposed training program is to foster the development of cancer prevention and control researchers through an intensive postdoctoral training program. The Specific Aims are 1) To provide postdoctoral fellows a specialized curriculum for education in cancer prevention and control, integrating behavioral, medical, biological, epidemiological, and community perspectives. 2) To teach postdoctoral fellows interdisciplinary research approaches in cancer prevention and control through hands-on participation in ongoing extramurally-funded research programs. 3) To foster the development of independent research careers in cancer prevention and control among postdoctoral fellows through both formal instruction and direct experience with writing research papers and grant applications with the guidance of their research mentoring team. Cancer is, and will continue to be, one of our greatest national health issues. Researchers trained in cancer prevention and control are a key element in combating both the incidence of and suffering associated with cancer. To that end, we propose to continue our successful postdoctoral training program to produce the next generation of independent cancer prevention and control researchers
Keywords: Accounting; Achievement; Address; Age; American; American Cancer Society; anticancer research; Applications Grants; Appointment; Area; Award; base; Behavior; Behavioral; Behavioral Mechanisms; Biological; Biological Process; Biology; Cancer Burden; Cancer Control; Cancer Control Research; cancer genetics; Cancer Patient; cancer prevention; career; Cause of Death; Cessation of life; combat; Communities; Complex; Development; Discipline; Educational aspects; Educational Curriculum; Educational process of instructing; Epidemiology; Evaluation; experience; Faculty; family influence; Fostering; Funding; Funding Agency; Funding Mechanisms; Generations; Goals; Grant; Guidelines; Health; improved; Incidence; Indium; Individual; innovation; Institute of Medicine (U.S.); Institution; Instruction; Interdisciplinary Study; Life Style; Malignant Neoplasms; Medical; Medicine; meetings; member; Mentors; Minority; multidisciplinary; National Cancer Institute; next generation; NIH Program Announcements; oncology; Paper; Positioning Attribute; post-doctoral training; Postdoctoral Fellow; prevent; Procedures; Program Effectiveness; programs; psychologic; Psychology; public health medicine (field); public health relevance; Publishing; Quality of life; Reporting; Research; Research Peer Review; Research Personnel; Research Training; response; risk perception; Scientist; Screening procedure; skills; Smoking; social; Social Class; Societies; success; Time; Training; Training Program for Cancer Prevention and Control Scientists (R25); Training Programs; United States; Writing
Relevance: Cancer is, and will continue to be, one of our greatest national health issues. Researchers trained in cancer prevention and control are a key element in combating both the incidence of and suffering associated with cancer. To that end, we propose to continue our successful postdoctoral training program to produce the next generation of independent cancer prevention and control researchers
Project start date: 1999-07-01
Project end date: 2015-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PAR-06-511
5R25CA081137-12 (2011): $531132
MICHIGAN DIABETES RESEARCH AND TRAINING CENTER
H William, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 3P60DK020572-32S3 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Michigan Diabetes Research and Training Center The Michigan Diabetes Research and Training Center (MDRTC) is a multidisciplinary unit of The University of Michigan Health System. The MDRTC is now in its thirtieth year, having been funded by the NIH/NIDDK since 1977. This application is for a seventh five-year continuation of funding for the period February 1, 2008 through January 31, 2013. The Center exists to meet the needs of investigators and thereby support and strengthen the University´s interdepartmental activities in research, training and outreach in the field of diabetes, its complications and related endocrine and metabolic disorders. The resources provided by the MDRTC have expanded and enriched the base of investigators involved in diabetes research, the Center´s most important resource, and have facilitated innovative multidisciplinary biomedical and translational research programs. The overall goals of the MDRTC are to 1. Facilitate and focus basic molecular and cellular research in the areas of diabetes, its complications and related endocrine and metabolic disorders. 2. Promote the application of relevant new knowledge to innovative, relevant, feasible, and cost-effective approaches to the prevention and control of diabetes and its complications through behavioral, clinical, epidemiologic, and health services research. 3. Evaluate, refine and disseminate new knowledge regarding diabetes, its complications, and related disorders into sustainable, widespread community practice, especially in communities at increased risk. 4. Recruit, train, motivate and retain an effective workforce of basic, clinical, epidemiologic, and health services investigators and health care providers in the areas of diabetes, endocrinology and metabolism
Keywords: Area; base; Behavioral; Clinical; Communities; Community Practice; cost effective; diabetes control; Diabetes Mellitus; Disease; Education and Outreach; Endocrine; Endocrinology; Epidemiology; Funding; Goals; Health Personnel; Health Services; Health Services Research; Health system; innovation; Knowledge; meetings; Metabolic Diseases; Michigan; Molecular; multidisciplinary; Prevention approach; programs; Recruitment Activity; Research; Research Personnel; Research Training; Resources; Risk; Training; Translational Research; Universities
Project start date: 2009-12-04
Project end date: 2011-11-30
Budget start date: 4-DEC-2009
Budget end date: 30-NOV-2011
PFA/PA: RFA-DK-06-014
3P60DK020572-32S3 (2010): $309000
3P60DK020572-33S1 (2010): $458000
BIOSYNTHETIC ANALYSIS OF MARINE CYANOBACTERIAL PATHWAYS
H William
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 2R01CA108874-06 from National Cancer Institute
Abstract: Marine cyanobacteria are extraordinarily rich in their production of biologically active and structurally unique natural products. A number of these secondary metabolites or their derivatives are lead compounds in drug development programs aimed at providing new therapies to treat cancer, bacterial infections, inflammatory responses and in crop protection to kill harmful microbial pathogens and insects. Isolation and structural analysis of marine and terrestrial cyanobacterial natural products has provided access to an unusually large number of mixed non-ribosomal peptide synthetase/polyketide synthase (NRPS/PKS) systems. The corresponding metabolic systems are comprised of an intriguing set of complex multifunctional proteins that along with allied enzymes generate structurally complex molecules via a modular multi-step process. Over the past several years the Sherman, Gerwick and Smith laboratories have developed a complementary program to clone and characterize the biosynthetic pathways of novel cyanobacterial secondary metabolites that possess significant potential for biotechnological applications. Despite considerable progress, a full understanding of the molecular mechanisms, catalytic activities, kinetic properties, and substrate specificities within cyanobacterial biosynthetic pathways is just beginning to unfold. The proposed research will build upon our accomplishments on the curacin, jamaicamide and cryptophycin/ arenastatin metabolic systems, three robust pathways that have been a rich source of new information. The expected metabolic, biochemical and structural understanding will facilitate the design of new biosynthetic systems that harness the growing potential of cyanobacterial natural product pathways. The full promise of cyanobacterial natural products to yield new lead compounds for development as useful pharmaceuticals will only be realized by closing a series of key gaps in knowledge and technology. Solving these challenges will require development and optimization of genetic and biochemical methods that allow us to 1) manipulate cyanobacterial natural product metabolic systems to produce analog structures, 2) utilize unique secondary metabolite enzymes for creation of novel bioactive molecules and, 3) screen new compounds and analogs to identify promising new anticancer compounds for further development. The specific aims are 1. To harness the inherent versatility of cyanobacterial natural product systems to create new anticancer lead compounds. Sub-aims include a. Investigate ability of cyanobacterial biosynthetic pathways to generate novel analogs using unique laboratory culture and mutasynthesis methodologies. b. Investigate the unique enzymatic capabilities of marine cyanobacterial pathways to engineer new metabolic systems and tailoring processes to generate new bioactive compounds. c. Employ structural biology and site-directed mutagenesis approaches to understand the precise biochemical mechanisms of unique biosynthetic enzymes. d. Develop new chemoenzymatic, in vivo, and in vitro pathways to create new anticancer agents with enhanced medicinal properties 2. Perform bioassays on new compounds resulting from Specific Aim 1. a. New compounds derived from the proposed research will be transferred to Eisai Research Institute and University of Michigan Center for Chemical Genomics for analysis of biological activity using a series of biochemical and cell based assays relevant to cancer. The proposed research will focus on elucidating the detailed function and mechanistic basis of complex biosynthetic pathways from marine cyanobacteria that create chemically diverse natural products with anti-cancer activity. The ability to understand and subsequently engineer these remarkable biochemical systems will create new opportunities to discover and develop effective drugs for the treatment of human diseases, particularly cancer and related metabolic disorders
Keywords: Ally; analog; Antineoplastic Agents; Bacterial Infections; base; Biochemical; Biological; Biological Assay; Biological Factors; Cells; Chemicals; Complex; Cryptophycin; Cyanobacterium; design; Development; drug development; Engineering; Enzymes; Genetic; Genomics; Grant; human disease; In Vitro; in vivo; Inflammatory Response; Insecta; Institution; Killings; Kinetics; Knowledge; Laboratories; Laboratory culture; Lead; Malignant Neoplasms; Marines; Metabolic; Metabolic Diseases; Methodology; Methods; Michigan; microbial; microorganism; Molecular; novel; Oceanography; pathogen; Pathway interactions; peptide synthase; Pharmaceutical Preparations; Pharmacologic Substance; polyketide synthase; Process; Production; programs; Property; Proteins; Research; Research Institute; Sequence Analysis; Series; Site-Directed Mutagenesis; Source; structural biology; Structure; Substrate Specificity; System; Technology; Universities
Relevance: The proposed research will focus on elucidating the detailed function and mechanistic basis of complex biosynthetic pathways from marine cyanobacteria that create chemically diverse natural products with anti-cancer activity. The ability to understand and subsequently engineer these remarkable biochemical systems will create new opportunities to discover and develop effective drugs for the treatment of human diseases, particularly cancer and related metabolic disorders
Project start date: 2004-07-01
Project end date: 2016-05-31
Budget start date: 14-SEP-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-10-067
2R01CA108874-06 (2011): $357809
HUNTINGTON´S DISEASE NATURAL PRODUCT DRUG DISCOVERY
H William, Professor
University Of California San Diegocity: La Jolla country: United States (us)
Grant 1R21AG038772-01A1 from National Institute On Aging
Abstract: Huntington´s Disease (HD) is a neurological disorder resulting from CAG triplet repeat genetic mutation of the IT15 gene that encodes the huntingtin protein. Extensive data in the field indicate that proteolytic fragment(s) of htt mediate the HD disease process, resulting in severe motor disturbances. The goal of this project will be to discover novel marine natural product compounds as potential therapeutic agents for Huntington´s disease (HD). This project fulfills a major gap in the HD and neurodegenerative disease field for discovery of novel agents as protease inhibitors for future development of therapeutic agents for HD. Furthermore, this project uses novel marine natural products as a unique opportunity for drug discovery in the protease target area to reduce production of neurotoxic htt proteolytic fragments that participate in HD. This unique project will integrate expertise in protease biochemistry and neurobiology by Dr. Vivian Hook, marine natural products for discovery of therapeutic agents by Dr. William Gerwick, and model striatal neuronal cells, as well as transgenic mice, expressing mutant huntingtin (htt) protein of Huntington´s disease by Dr. Albert La Spada at the Univ. of Calif., San Diego. The project plan will implement interdisciplinary efforts of three highly experienced laboratories in the required disciplines to discover novel protease inhibitors of huntingtin protein proteolysis as a means to reduce cellular mutant htt neurotoxicity. This project can progress at a rapid pace since the collaborating laboratories have the required expertise, and are located in close proximity to one another at UC San Diego. HD drug discovery of this project will be accomplished in two specific aims. The first aim will evaluate marine natural product compounds for inhibition of protease activities thought to be involved in HD, which includes caspase, calpain, lysosomal proteases (cathepsins L, B, and D), and matrix metalloprotease 10. Cyanobacteria algal marine natural product compounds are a rich source of potent drug molecules with unique structural diversity. In aim 2, cyanobacterial marine natural compounds will be tested in cellular assays for reduction of N-terminal htt fragments and protection from cell death, using striatal-like neuronal cells that express full-length mutant huntingtin (htt) protein, and in control cells expressing normal htt protein. Effective compounds identified from aims 1 and 2 will be prioritized by their inhibitory potencies. These compounds will be planned for a future R01 project that will conduct in vivo testing of compounds in HD mouse models for effectiveness to improve the motor impairment in HD transgenic mice. Results can indicate candidate marine natural drug compounds for HD drug development. Huntington´s Disease (HD) is a neurological disorder resulting in motor disturbances as well as dementia. The goal of the proposed new project will be to discover novel therapeutic agents for Huntington´s disease (HD). This unique project will integrate the joint expertise of three experts in protease and cellular biochemistry, marine natural product drug discovery, and cellular with genetic mouse models of HD by Dr. Vivian Hook, Dr. William Gerwick, and Dr. Albert La Spada, respectively, at the Univ. of Calif., San Diego that will facilitate development of therapeutic agents for HD
Keywords: Affect; Algae; Area; attenuation; Behavioral; Biochemical; Biochemistry; Biological Assay; Biological Factors; Brain region; Calpain; caspase; caspase-6; Cathepsin L; Cell Death; Cell Line; Cells; Cellular Assay; Chemicals; Chemistry; Cleaved cell; Collection; Corpus striatum structure; Cyanobacterium; Data; Dementia; Development; Discipline; Disease; Drug Compounding; drug development; drug discovery; drug testing; Effectiveness; Evaluation; experience; Future; Gene Mutation; Genetic; Goals; Hereditary Disease; human Huntingtin protein; Huntington Disease; Huntington gene; Impaired cognition; improved; in vitro testing; in vivo; Inherited; inhibitor/antagonist; Inhibitory Concentration 50; Joints; Kinetics; Knowledge; Laboratories; Length; marine natural product; Marines; Mediating; Metalloproteases; Modeling; Molecular; Monitor; Motor; motor impairment; mouse model; mutant; N-terminal; Natural Product Drug; nervous system disorder; Neurobiology; neurochemistry; Neurodegenerative Disorders; neuron loss; Neurons; neurotoxic; neurotoxicity; novel; novel therapeutics; Pathogenesis; Pathology; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Principal Investigator; Process; Production; Protease Inhibitor; Proteolysis; relating to nervous system; Relative (related person); Research; Screening procedure; Small Interfering RNA; small molecule; Source; Testing; Therapeutic Agents; Transgenic Mice; Trinucleotide Repeats; Western Blotting
Relevance: Huntington´s Disease (HD) is a neurological disorder resulting in motor disturbances as well as dementia. The goal of the proposed new project will be to discover novel therapeutic agents for Huntington´s disease (HD). This unique project will integrate the joint expertise of three experts in protease and cellular biochemistry, marine natural product drug discovery, and cellular with genetic mouse models of HD by Dr. Vivian Hook, Dr. William Gerwick, and Dr. Albert La Spada, respectively, at the Univ. of Calif., San Diego that will facilitate development of therapeutic agents for HD
Project start date: 2011-09-01
Project end date: 2013-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PAR-10-002
1R21AG038772-01A1 (2011): $190035
Sponsored Links Excellgen http://Excellgen.com
AIDS-RESTRICTIVE INNATE IMMUNE MECHANISMS
H William, Instructor Of Medicine
Massachusetts General Hospitalcity: Boston country: United States (us)
Grant 5K01TW007793-04 from Fogarty International Center
Abstract: HIV-1 disease is a serious international health problem and a major cause of death in sub-Saharan Africa. Therapeutic and preventative treatments are limited in availability and effectiveness, thus critical evaluations of alternative approaches to control this virus are greatly needed. The overall goal of this project is to elucidate the mechanisms underlying naturally occurring protective immunity to HIV-1 disease in sub- Saharan Africa. The specific aims are (1) to determine the role of NK-cells in decreasing mother to child HIV- 1 transmission and in slowing HIV-1-disease progression to AIDS in adults and (2) to determine the molecular mechanisms of HLA-Bw4 80! mediated protection from HIV transmission and disease progression. In the first aim we will conduct a cross-sectional study by collecting peripheral blood samples from mothers who are HIV-transmitters versus non-transmitters and assessing their NK-cell responses to HIV-infected self and child-derived T cells by the production of anti-viral soluble factors (e.g., interferon-y, MIP-1a & (3, and RANTES) as well as by cell-killing assays. We will also conduct a similar analysis with blood samples from HIV-1-infected adults that are virus controllers compared to virus non-controllers. To address the second aim we will generate reporter cells expressing NFAT-LacZ and the NK cell receptor, KIR3DS1. We will assess HLA-B recognition by KIR3DS1 by in vitro co-culture assays with HIV-1 infected and uninfected target cell lines expressing the putative ligand, HLA-B57. To probe molecular mechanisms of recognition by KIR3DS1 further, HLA mutagenesis or HIV peptide screening will be employed. The research plan is ideal for the career objective of the candidate, William Carr, to become an independent investigator in international health research, specializing in innate viral immunity. The proposed career development plan will consist of closely mentored basic-science research with Drs. Marcus Altfeld and Bruce Walker as mentors in the U.S. and Drs. Hoosen Coovardia and Salim Abdool Karim as a mentors in South Africa, state-of-the-art research facilities at the Doris Duke Research Center in Durban, South Africa, and at the Partners AIDS Research Center at Massachusetts General Hospital in the U.S., and a didactic curriculum on ethics in international research. This plan is well suited for Dr. Carr to establish long-term scientific collaborations in South Africa and to establish himself as an independent investigator in international health research
Keywords: Acquired Immunodeficiency Syndrome; Address; Adult; Affect; Africa South of the Sahara; African; AIDS/HIV problem; Alleles; antiretroviral therapy; Area; base; Basic Science; Biological Assay; Blood specimen; career; career development; Cause of Death; cell killing; Cell Line; Cell Surface Proteins; Cell Surface Receptors; Cells; Child; Coculture Techniques; Collaborations; Cross-Sectional Studies; Development; Development Plans; Disease; Disease Outcome; Disease Progression; Drug resistance; drug resistant virus; Educational Curriculum; Effectiveness; Environment; Ethics; Ethnicity aspects; Evaluation; General Hospitals; Genetic; Goals; Health; Highly Active Antiretroviral Therapy; HIV; HIV-1; HLA Antigens; HLA-B57; HLA-Bw4; Human; Immune; Immune response; Immune Response Genes; Immune system; Immunity; Immunoglobulins; Immunologic Receptors; In Vitro; Individual; Infection; Interferons; International; International Health Problems; Isoleucine; Killer Cells; KIR3DS1; LacZ Genes; Ligands; Lymphocyte; Massachusetts; Mediating; Medical Research; Mentors; Molecular; Molecular Probes; Mothers; Mutagenesis; Natural Killer Cells; novel; Pathogenicity; Peptides; peripheral blood; Play; Population; Positioning Attribute; Pregnancy; pressure; Prevalence; Production; RANTES; receptor; Receptor Gene; Reporter; Research; research facility; Research Infrastructure; Research Personnel; Research Support; response; Role; Sampling; Screening procedure; Site; Small Inducible Cytokine A3; South Africa; T-Lymphocyte; Testing; Therapeutic; transmission process; Universities; Variation (Genetics); Vertical Disease Transmission; Viral; Viral Load result; Virus; Walkers
Project start date: 2007-12-01
Project end date: 2011-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PAR-07-014
5K01TW007793-04 (2011): $122332
GENETICALLY ENGINEERED MOUSE FACILITY
H William
University Of Texas Md Anderson Can Ctrcity: Houston country: United States (us)
Abstract: Genetically engineered mice have become the "gold standard" for animal models in cancer. They are widely used to mimic human cancers with specific point mutations in tumor suppressor genes, as well as tissuespecific expression of mutations in somatic tissues. By combining several mutations in one animal, it is now possible to phenocopy human cancers that were difficult to reproduce previously in animal models. The Genetically Engineered Mouse Facility (GEMF) provides valuable resources to Cancer Center members. It generates transgenic and gene-targeted mice, performs embryo rederivations to generate pathogen-free mice, and provides cryopreservation services to archive animal models. The Mouse Resource Facility (MRF), as part of the GEMF, provides vectors for construct development, northern blots of adult and embryonic tissues, genomic DNA and cDNA libraries, and BAG filter sets. The MRF also has a small colony of Cre and lacZ transgenic mice essential for generating conditional deletions in mice. The GEMF thus provides unique opportunities to faculty to develop sophisticated animal models to study a variety of cancer problems. The GEMF has been extremely successful in generating and maintaining mouse models. In the last five years, the GEMF has generated animal models for more than 300 projects for MDACC investigators and has cryopreserved more than 120 mouse lines. A >1000% increase has been achieved in utilization of mouse resources through the MRF. The lead facility coordinator has developed new, more efficient methods of generating embryos for use by the facility. She is responsible for training faculty and their staff, and provides genetic and technical expertise to many investigators in many different programs. In addition to the facility coordinator, the GEMF is staffed by 7 highly-trained technicians. In the past five years, the GEMF has served 96 different users who represent 19 of the 20 sponsored programs; 97% of the investigators served are MDACC faculty. To better serve the needs of our investigators and add needed capacity, a small satellite facility was added recently to the South Campus. This expansion will enable the GEMF to develop more models and offer additional services. The GEMF is currently funded from multiple sources, including 53% provided by the CCSG and 45% recovered through user fees, with the remainder provided by MDACC
Keywords: Adult; Advertising; Animal Model; Animals; Archives; Bacterial Artificial Chromosomes; blastocyst; Cancer Center; Cancer Center Support Grant; cDNA Library; Complex; Cryopreservation; Derivation procedure; Detection; Development; DNA Library; Embryo; embryo tissue; embryonic stem cell; Faculty; Fees; flexibility; Funding; Gene Targeting; Generations; Genes; Genetic; Genetic Engineering; Genetically Engineered Mouse; Genomics; germ free condition; Gold; Growth; Human; Immunology; in vivo; Injection of therapeutic agent; LacZ Genes; Lead; Malignant Neoplasms; meetings; member; Methods; Mission; Modeling; mouse genome; mouse model; Mus; Mutation; Northern Blotting; pathogen; Phenocopy; Phenotype; plasmid DNA; Point Mutation; Procedures; Processed Genes; programs; Reagent; Reproductive Immunology; Research Personnel; Resources; Services; Source; Specific Pathogen Frees; Technical Expertise; Techniques; Testing; Time; Tissues; Training; Transgenic Mice; Transgenic Organisms; tumor; Tumor Suppressor Genes; University of Texas M D Anderson Cancer Center; Variation (Genetics); vector
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P30CA016672-36_9031 (2011): $538985
CBT TRAINING FOR CLINICIANS PROVIDING SUPPORTIVE CARE FOR CANCER SURVIVORS
H William, Professor
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 5R25CA138494-03 from National Cancer Institute
Abstract: For between one-third and one-half of all cancer survivors, disturbances in mood and cognition do not end with the conclusion of treatment. Recognizing this problem, the Institute of Medicine (IOM) has emphasized in its 2007 report, "Cancer Care for the Whole Patient Meeting Psychosocial Health Needs," the importance of addressing psychosocial issues, such as distress, to providing good cancer care. The NCI has recognized that there is a severe lack of trained professionals to address these needs. The proposed training program seeks to reduce these quality of life problems by training health professionals providing supportive care to cancer survivors to implement of Cognitive-Behavioral Therapy (CBT). Empirically-validated CBT interventions have been found to yield significant benefits for cancer patients and survivors, including reduction of psychological distress. Although 71% of health care professionals we polled recognized the usefulness of CBT, only 5% reported mastery of CBT skills. And over 80% expressed high motivation in learning how to implement CBT techniques targeted for cancer survivors. Trainees will be competitively selected licensed/credentialed professionals, including psychologists, social workers, and CL nurses. The proposed R-25E will test a structured CBT training curriculum that includes didactic discussion, role playing and feedback. The curriculum will be presented across 3-day workshops with 40 trainees at each workshop (for a total of 320 trainees across a total of 8 workshops). CBT workbooks and copies of relevant journal articles and review chapters will be provided. After completing the workshop, trainees will participate in six monthly follow-up group phone conferences to review CBT techniques and to discuss their progress. Program evaluation will address knowledge and skills acquired, survivor benefit, trainee and institutional up-take, and trainee satisfaction. Overarching goal to train healthcare professionals to implement CBT for cancer survivors in order to improve their quality of life. Specific aims 1 To test the effectiveness of healthcare professional CBT training workshops using paper-and-pencil evaluations of trainee knowledge of CBT techniques, administered pre- and post-workshops; 2 To assess CBT skills gained based on trainer ratings of trainee skill during mock CBT sessions carried out during workshops; 3 To evaluate the effectiveness of training based on trainer assessment of skill demonstrated during presentation of a case presented after the sixth (and final) follow-up phone conference call; 4 To determine the effectiveness of training in terms of benefit for end-users, the survivors treated by trainees, as determined by survivors´ ratings of distress on standardized measures completed before and after the CBT intervention; 5 To evaluate trainee uptake of CBT through an assessment of their continued implementation of CBT with survivors after completion of all training; 6 To determine institutional uptake of the CBT training as indicated by the institution´s intention to send other staff members to future CBT training workshops; 7 To assess trainee satisfaction with the CBT professional education program. Relevance Even after treatment is over, many cancer survivors continue to suffer from emotional distress. The proposed professional cancer education program strives to provide these survivors the best possible care by training the clinicians responsible for their supportive services to implement Cognitive-Behavioral Therapy
Keywords: active method; Address; Aftercare; Anxiety; base; behavior test; Behavioral; Belief; California; cancer care; cancer education; Cancer Patient; Cancer Survivor; Caring; Cities; clinically significant; Cognition; Cognitive Therapy; Collaborations; Consultations; Counseling; design; Discipline of Nursing; Distress; Educational Curriculum; Educational process of instructing; Educational workshop; Effectiveness; emotional distress; Evaluation; experience; Feedback; Feeling; follow-up; Future; Goals; Health; Health Professional; Health Psychology; improved; Institute of Medicine (U.S.); Institution; Intention; Intervention; journal article; Knowledge; Learning; Licensing; Malignant Neoplasms; medical schools; meetings; member; Mental Depression; Methods; Moods; Motivation; New York; Nurses; Paper; Patients; Physiological; Population; Professional Education; Program Evaluation; programs; psychological distress; Psychologist; psychosocial; Psychosocial Influences; Quality of life; Reaction; Reporting; Research Personnel; response; Role playing therapy; satisfaction; Services; skills; skills training; Social work (field); Social Workers; standardize measure; Structure; Supportive care; Survivors; symposium; Symptoms; Techniques; Telephone; Testing; Training; Training Programs; uptake
Relevance: Relevance: Even after treatment is over, many cancer survivors continue to suffer from emotional distress. The proposed professional cancer education program strives to provide these survivors the best possible care by training the clinicians responsible for their supportive services to implement Cognitive-Behavioral Therapy
Project start date: 2009-09-01
Project end date: 2014-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PAR-08-120
5R25CA138494-03 (2011): $314079
PYK2 FUNCTION DURING FERTILIZATION
H William, Professor
University Of Kansas Medical Centercity: Kansas City country: United States (us)
Grant 5R01HD062860-02 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Fertilization involves a series of signal transduction events that serve to activate the block to polyspermy, induce resumption of the cell cycle, incorporate the paternal genome, and activate egg metabolism. Key steps in this process include the actin cytoskeleton modifications that physically incorporate the sperm nucleus into the egg and subsequently reorganize the egg cortex. Recent findings by this laboratory revealed that the cytoskeleton-associated PYK2 kinase is rapidly activated during fertilization and functional studies indicate a role for PYK2 in sperm incorporation and egg activation. The objective of the proposed study is to test the hypothesis that PYK2 kinase participates in the signaling events triggered by sperm-egg adhesion or fusion that are critical for sperm incorporation and modification of the egg cytoskeleton. The project will make use of the economical zebrafish fertilization system which provides unique advantages for identification of signaling events at the point of sperm-egg contact as well as for proteomic analysis of substrates of the PYK2 kinase. The first specific aim will identify the specific function(s) of PYK2 kinase in egg activation. The second aim will identify the signals which activate PYK2 at fertilization. The third aim will identify the protein targets phosphorylated by PYK2 in order to work out the downstream pathways that it controls. The results of this study will provide important details regarding control of the egg cytoskeleton at fertilization and possibly help resolve the question of signaling pathways activated by sperm-egg recognition and fusion. These findings will have significant application to the development of techniques for assisted reproductive technologies to enhance human fertility. Lay Summary This study will work out the mechanism by which the sperm activates the egg during fertilization. The specific role of PYK2 kinase in bringing the sperm nucleus into the egg will be analyzed with the ultimate aim of enhancing the success of human in vitro fertilization. Assisted reproductive technologies such as in vitro oocyte maturation, in vitro fertilization and intracytoplasmic sperm injection have remained fairly inefficient processes. The proposed experiments will provide basic knowledge regarding the signal transduction process initiated by sperm-egg contact which could be used to improve these clinical methods
Keywords: Actins; Adhesions; Assisted Reproductive Technology; base; Binding (Molecular Function); Biochemical Pathway; Calcium; Calcium Channel; Calcium Signaling; Cell Cycle; Cell membrane; Cell Nucleus; cell type; Cells; Chromatin; Clinical; Competence; Cytoskeletal Modeling; Cytoskeleton; Development; Dominant-Negative Mutation; egg; Event; Fertility; Fertilization; Fertilization failure; Fertilization in Vitro; functional restoration; Genome; Germ Cells; Goals; Guanosine Triphosphate; Human; human PTK2B protein; Image; Immunoprecipitation; improved; In Vitro; Individual; inhibitor/antagonist; Insemination; Integrins; Intracytoplasmic Sperm Injections; Knowledge; knowledge base; Laboratories; Laboratory Finding; Left; Mediating; Membrane Proteins; Metabolism; Methods; Modeling; Modification; Mus; NAADP; novel; nuclear transfer; oocyte maturation; Oocytes; Ooplasm; Outcome Study; particle; Pathway Analysis; Pathway interactions; Performance; Phosphoproteins; Phosphorylation; Phosphotransferases; Procedures; Process; Proteins; Proteomics; PTK2B gene; public health relevance; Reagent; Recombinant Proteins; Reproduction; research study; response; Retinal Cone; Role; Running; Series; Signal Pathway; Signal Transduction; Site; sperm cell; Staging; success; Surface; System; technique development; Testing; Time; Translating; Western Blotting; Work; Zebrafish; zygote
Relevance: Assisted reproductive technologies such as in vitro oocyte maturation, in vitro fertilization and intracytoplasmic sperm injection have remained fairly inefficient processes. The proposed experiments will provide basic knowledge regarding the signal transduction process initiated by sperm-egg contact which could be used to improve these clinical methods
Project start date: 2010-08-13
Project end date: 2015-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01HD062860-02 (2011): $259200
MODIFICATION OF EGG PLASMA MEMBRANE
H William, Professor
University Of Kansas Medical Centercity: Kansas City country: United States (us)
Grant 5R01HD014846-29 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Fertilization in species that utilize external fertilization, including model systems such as sea urchin, frog, and fish, all exhibit rapid protein tyrosine kinase (PTK) activation as a critical step required for the sperm- induced calcium transient, exit from meiosis II, pronuclear congression, and mitosis. Recent studies have demonstrated that mammalian eggs differ from lower species as to the mechanism controlling the sperm- induced calcium transient. However, while studies in oocytes of mice and rats indicate that Src-family kinase activity is not required for calcium signaling, there is strong evidence that these kinases play a role in Mil resumption and pronuclear congression. The main goals of this proposal are to establish which Src-family kinases are required signaling pathways critical to MM resumption and pronuclear congression. The first specific aim will test the hypothesis that individual Src-family PTKs (Fyn, Yes, or Src) are required for resumption of meiosis and pronuclear congression. The experimental approach will use a combination of Src-family knockout mice and dominant-negative constructs to define the role of each kinase in these processes. The Second aim will identify the specific biochemical pathways in which these kinases participate to accomplish each function. Here biochemical analyses will establish which pathways have been interrupted by suppression of each individual kinase Fyn, Yes, and Src. The relationship of each pathway to MM resumption of pronuclear congression will be established. The third specific aim will test the hypothesis that Fyn, Yes, and Src are differentially regulated after fertilization and that their activity increases at specific points during egg activation that allow them to control MM resumption and pronuclear congression. This aim will also identify the regulatory mechanisms by which these kinases are activated in the fertilized egg. The results of this study will provide an understanding of the biochemical mechanisms regulating MM resumption and pronuclear congression and will lead to future studies enabling us to modulate these processes artificially. Lay Summary Fertilization requires that multiple enzymes become turned on in order for the egg to grow into an embryo. This study will use more sensitive, modern techniques to establish which protein kinases trigger the fertilized egg to eject extra chromosomes and move the male and female nuclei together
Keywords: Activation Analysis; Analyses, Activation; Anaphase; anaphase-promoting complex; Antibodies; Antimorphic mutation; ATP-protein phosphotransferase; ATP[{..}]protein-tyrosine O-phosphotransferase; Biochemical; Biochemical Pathway; Biological Models; Blood Coagulation Factor IV; Breeding; Ca++ element; Calcium; Calcium Ion Signaling; Calcium Signaling; Cell Cycle; Cell Division Cycle; Cell membrane; Cell Nucleus; Chromosomes; Coagulation Factor IV; Common Rat Strains; Critical Paths; Critical Pathways; cycB2; cyclin B2; cyclosome; Cytoplasmic Membrane; Defect; Development; Dominant Negative; Dominant-Negative Mutant; Dominant-Negative Mutation; EC 2.7; Echinoidea; egg; Embryo; Embryonic; Enzymes; EPH- and ELK-Related Tyrosine Kinase; EPH-and ELK-Related Kinase; EPHA8; EphA8 Protein; Ephrin Type-A Receptor 8; Ephrin Type-A Receptor 8 Precursor; Event; Exhibits; Factor IV; Family; Female; Fertility/Fertilization; Fertilization; Fertilized Egg; Fertilized Ovums; Fishes; Frog; functional restoration; Future; G1/S Transition; G2/Mitotic-Specific Cyclin B2; gene product; glycogen synthase a kinase; Goals; heavy metal lead; heavy metal Pb; HEK3; hydroxyalkyl protein kinase; hydroxyaryl protein kinase; ICSI; Immunofluorescence; Immunofluorescence Immunologic; Immunologic, Immunofluorescence; Individual; insight; Intracytoplasmic Sperm Injections; Investigators; Kinases; Knock-out; Knockout; Knockout Mice; knowledge base; language translation; Lead; Length; Location; M Phase; M phase (cell cycle); male; Mammalia; Mammals; Mammals, General; Mammals, Mice; Mammals, Rats; Marine Invertebrates; Measures; Meiosis; meiotic; Metabolic Networks; Method LOINC Axis 6; Methodology; Methods; Methods and Techniques; Methods, Other; Mice; Mice, Knock-out; Mice, Knockout; Mitosis; Mitosis Stage; Mitotic Anaphase; Model System; Models, Biologic; Modification; Murine; Mus; novel; Nuclear Envelope; Nuclear Membrane; nuclear transfer; nuclear transplantation; Nucleus; Null Mouse; Oocytes; Outcome Study; Ovocytes; Ovum, Fertilized; pathway; Pathway interactions; Pb element; Phase; phosphorylase b kinase kinase; Phosphorylation Site; Phosphotransferases; Plasma Membrane; plasmalemma; Play; Procedures; Process; programs; Programs (PT); Programs [Publication Type]; Protein Kinase; Protein Tyrosine Kinase; Protein Tyrosine Kinase EEK; Protein-Tyrosine Kinases, src; Proteins; PTK; Rana; Rana (genus); Rat; Rattus; Reagent; Regulation; Regulatory Pathway; Research Personnel; Researchers; restore function; restore functionality; restore lost function; Role; Sea Urchins; Signal Pathway; social role; Sperm; sperm cell; Sperm Injections, Intracytoplasmic; Spermatozoa; src Kinases; src Tyrosine Kinases; src-Family Kinases; src-Family Tyrosine Kinases; Staging; Structure of zygote; success; System; System, LOINC Axis 4; Techniques; Testing; Time; time interval; Translating; Translatings; Transphosphorylases; Tyrosine Kinase; Tyrosine-Protein Kinase Receptor EEK; Tyrosine-Specific Protein Kinase; tyrosyl protein kinase; Tyrosylprotein Kinase; vertebrata; Vertebrate Animals; Vertebrates; Wild Type Mouse; Work; zoosperm; zygote; Zygote
Project start date: 1997-01-01
Project end date: 2012-02-29
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
5R01HD014846-29 (2011): $210507
DNA-DIRECTED EFFECTS OF FDUMP(N)
H William, Professor
Wake Forest University Health Sciencescity: Winston-salem country: United States (us)
Grant 5U01CA102532-05 from National Cancer Institute
Abstract: FdUMP[N] compounds constitute a novel class of fluoropyrimidine (FP) chemotherapeutic that may be useful for the treatment of human malignacies that are refractory to current chemotherapy. The goal of this research project is to understand the unique cytotoxic mechanism of FdUMP[N] compounds. Human prostate cancer (PC) cells will be used as a model system to investigate FdUMP[N] cytotoxicity because of the relative sensitivity of PC cells to FdUMP[10], and because of the need for new and more effective drugs to treat late-stage PC. PC results in nearly 30,000 deaths in the U.S. each year. Aim 1 focuses on evaluating the extent that FdUMP[N] multimers enter PC cells via active transport and identifying proteins expressed by PC cells that are involved in receptor-mediated endocytosis. Cellular uptake kinetics will be determined from the time- and concentration-dependence of radioactivity in PC cellular lysates following exposure to 32P-labeled FdUMP[N] compounds. The contribution of active transport to cellular uptake will be evaluated using metabolic inhibitors. Structure/function analyses will be performed to identify structural features of FdUMP[N] compounds that promote intracellular internalization of FdUMP[N] compounds via active transport. Protein(s) involved in the active transport of FdUMP[N] compounds will be identified by UV cross-linking, and sequences for these protein(s) will be determined using mass spectrometry. In Aim 2, the intracellular metabolism of [6-3H]FdUMP[N] compounds to monomeric FP metabolites will be evaluated, and thymidylate synthase inhibition and nucleotide pool imbalances will be quantified. In Aim 3, the misincorporation of FdUTP into DNA and the extent and type of DMA damage, including DNA damage resulting from topoisomerase I cleavage complex formation, will be quantified using alkaline elution, pulsed-field gel electrophoresis, and an in vivo complex of enzyme bioassay. These studies greatly enrich our understanding of the unique cytotoxic mechanism for FdUMP[N] compounds towards PC cells
Keywords: (S)-4-ethyl-4-hydroxy-1H-pyrano-[3`, 4`[{..}]6, 7]indolozino[1, 2-b]quinoline-3, 14(4H, 12H)-dione; 1H-Pyrano(3`, 4`[{..}]6, 7)indolizino(1, 2-b)quinoline-3, 14(4H, 12H)-dione, 4-ethyl-4-hydroxy-, (S)-; 1H-Pyrano[3`, 3`.6, 7]indolizino[1, 2-b]quinoline-3, 14(4H, 12H)-dione, 4-ethyl-4hydroxy-(S)-(9CI); 2, 4-Dioxo-5-fluoropyrimidine; 2, 7-Naphthalenedisulfonic acid, 3, 3`-((3, 3`-dimethyl(1, 1`-biphenyl)-4, 4`-diyl)bis(azo))bis(5-amino-4-hydroxy-), tetrasodium salt; 2-Deoxy-D-glucose; 2-Deoxyglucose; 2-Desoxy-D-glucose; 2-Propanol; 20-(S)-camptothecine; 21, 22-secocamptothecin-21-oic acid lactone; 5`-Deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine; 5`-Uridylic acid, 2`-deoxy-5-fluoro-; 5, 10-Methylenetetrahydrofolate[{..}]dUMP C-methyltransferase; 5-Fluoro-2`-Deoxyuridine-5`-Monophosphate; 5-Fluoro-2, 4(1H, 3H)-pyrimidinedione; 5-Fluorouracil; 5-Fluracil; 5-FU; 5FU; Active Biological Transport; Active Transport; Affinity; Amino Acid Sequence; Analysis, Data; Anti-Cancer Agents; Anti-Tumor Agents; Anti-Tumor Drugs; anticancer agent; anticancer drug; Antineoplastic Agents; Antineoplastic Drugs; Antineoplastics; Antiproliferative Agents; Antiproliferative Drugs; Apoptotic; Assay; Athymic Nude Mouse; base; Benzamine Blue; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biologic Transport, Active; Biological Assay; Biological Models; Biological Transport, Active; C34H28N6O14S4; Camptothecin; cancer cell; Cancer cell line; Cancer Drug; Cancer of Prostate; Cancers; capecitabine; Cell Cycle Arrest; Cell Death; Cell Line; Cell Lines, Strains; Cell model; Cell/Tissue, Immunohistochemistry; CellLine; Cells; Cellular model; Cessation of life; Charge; chemical structure function; Chemicals; Chemotherapeutic Agents, Neoplastic Disease; chemotherapy; clinical investigation; Clinical Trials; Clinical Trials, Unspecified; Collaborations; Colon Cancer; Colon Carcinoma; Colonic Carcinoma; Comet Assay; Complex; computerized data processing; Confocal Microscopy; cross-link; crosslink; cultured cell line; Cytofluorometry, Flow; cytotoxic; cytotoxicity; D-arabino-Hexose, 2-deoxy-; Data; Data Analyses; data processing; Death; density; Deoxyglucose; Deoxyribonucleic Acid; Dependence; Development; DNA; DNA Damage; DNA Double Strand Break; DNA Injury; DNA Nicking-Closing Protein; DNA Relaxing Enzyme; DNA Relaxing Protein; DNA Single Strand Break; DNA Topoisomerase I; DNA Topoisomerases, Type I; DNA Type 1 Topoisomerase; DNA Untwisting Enzyme; DNA Untwisting Protein; DNA-protein crosslink; drug/agent; Drugs; dTMP Synthase; DU145; EC 2.1.1.45; Electrophoresis, Gel, Pulsed-Field; Electrophoresis, Gel, Pulsed-Field Gradient; enzyme complex; Epithelium of Human Prostate Gland; Exclusion; exposed human population; Exposure to; FdUMP; Flow Cytofluorometries; Flow Cytometry; flow cytophotometry; Flow Microfluorimetry; Fluoro Uracil; Fluorodeoxyuridylate; fluoropyrimidine; Fluorouracil; Fluoruracil; Fluouracil; Fractionation, Pulse Field; Gel Electrophoresis, Single-Cell; gene product; Goals; Head; hepatoma cell; Human; human exposure; Human, General; IHC; Immunohistochemistry; Immunohistochemistry Staining Method; in vivo; inhibitor; inhibitor/antagonist; innovate; innovation; innovative; insight; Intermediary Metabolism; Investigators; Isopropanol; Isopropyl Alcohol; Kinetic; Kinetics; Label; Laboratories; Length; Lytotoxicity; malignancy; Malignant Cell; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Malignant Neoplasms; Malignant Pancreatic Neoplasm; Malignant prostatic tumor; Malignant Tumor; Malignant Tumor of the Prostate; Man (Taxonomy); Man, Modern; Mass Spectrum; Mass Spectrum Analysis; Measures; Mediating; Medication; Metabolic; Metabolic Processes; Metabolism; METBL; Methods and Techniques; Methods, Other; Mice, Athymic; Mice, Nude; Microfluorometry, Flow; Model System; Models, Biologic; Molecular Biology, Protein Sequencing; Molecular Interaction; Molecular Transport; Multienzyme Complexes; N(4)-pentyloxycarbonyl-5`-deoxy-5-fluorocytidine; NaN3; necrocytosis; neoplasm/cancer; nicking closing enzyme; NMR Spectroscopy; novel; Nuclear; nuclear magnetic resonance spectroscopy; Nucleotides; Nude Mice; Pancreas Cancer; Pancreatic Cancer; pathway; Pathway interactions; PC3 cell line; Peptide Sequence Determination; PFGE; Pharmaceutic Preparations; Pharmaceutical Preparations; Photometry/Spectrum Analysis, Mass; poison; Poisons; pre-clinical; Precipitation; preclinical; Primer Extension; Process; programs; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Prostate CA; Prostate Cancer; prostate cancer cell line; Prostatic Cancer; Prostatic Epithelium; protein sequence; Protein Sequencing; Protein Structure, Primary; Proteins; Protocols, Treatment; prototype; Publishing; Qualifying; R01 Mechanism; R01 Program; Radioactivity; receptor mediated endocytosis; Refractory; Regimen; Relative; Relative (related person); relaxing enzyme; Reporting; Research; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Researchers; RGM; RPG; Rubbing Alcohol; Scintillation Counting; Sequence Determinations, Amino Acid; Sequence Determinations, Protein; signal processing; Site; Sodium Azide; Spectrometry, Mass; Spectroscopy, Mass; Spectroscopy, NMR; Spectrum Analyses, Mass; Spectrum Analysis, Mass; Staging; Structure; structure function relationship; Structure-Activity Relationship; swivelase; Techniques; Thymidylate Synthase; Thymidylate Synthetase; Time; TMP synthetase; Topoisomerase I; Toxic Chemical; toxic compound; Toxic Substance; Transport Process; Treatment Protocols; Treatment Regimen; Treatment Schedule; Trypan Blue; tumor xenograft; Tumor-Specific Treatment Agents; TYMS; Type I DNA Topoisomerases; untwisting enzyme; Uphill Transport; uptake; Work; Xeloda
Project start date: 2005-08-10
Project end date: 2011-07-31
Budget start date: 1-AUG-2009
Budget end date: 31-JUL-2011
5U01CA102532-05 (2009): $300196
UCLA CENTER FOR BIOLOGICAL RADIATION MITIGATORS
H William, Professor Of Radiation Oncology
University Of California Los Angelescity: Los Angeles country: United States (us)
Grant 5U19AI067769-07 from Office Of The Director, National Institutes Of Health
Abstract: Despite the long history of studying the effects of radiation on normal tissues in vitro and in vivo, there is a dearth of agents immediately available for mitigating radiation injury. The UCLA-CMCR has developed an infrastructure that allows discovery and evaluation of such agents. Most of this effort went into an unbiased approach to drug discovery that employs high throughput screening (HTS) of libraries of chemically defined or known bioactive small molecules using yeast, murine, and human systems and multiple endpoints. Importantly, Projects 1 and 2, which will continue, identified lead compounds and classes of compounds from both types of libraries that can mitigate damage in vivo when given to mice 24 hrs after lethal whole body radiation doses. "Core" chemical structures have been identified, so part of the focus in the next funding period will be on synthesizing analogues to hone in on the critical elements responsible for activity, with a view to optimizing drug effectiveness and delivery through pharmaceutical chemistry. We have validated our original concept that molecular and chemical "signatures" can be used to classify modulators of radiation responses and that these can then be exploited for rational development of effective mitigating agents. We have knowledge of mechanisms for several classes of compounds, but several others still need to be further investigated. Some act through Toll-like receptors, as described in this application, and Project 3 now focuses on this pathway. Further drug discovery efforts are underway. The UCLA-CMCR has harnessed multiple strengths at UCLA with benefit to the CMCR program and has built a rich environment for research, training, and product development in the radiation sciences. This renewal incorporates investigators, information, and experimental systems from eight pilot projects, in addition to existing personnel. All information is stored on an industrial-strength database so that all CMCRs can have access for analysis and data mining. We interact with other members of the CMCR network and with groups and individuals in academic and commercial entities to test and compare mitigators. In brief, the UCLA-CMCR has made great progress and has developed many promising avenues for future exploration
Relevance: RELEVANCE: There are few agents that can be given to radiation exposed individuals to mitigate harm. This program has developed new mitigators by screening tens of thousands of compounds for effectiveness. The lead compounds that have been identified will now be further tested and examined for efficacy, ease of delivery, and safety so that they can be readily given to the public in a radiological emergency
Project start date: 2005-08-31
Project end date: 2015-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-AI-09-036
5U19AI067769-07 (2011): $3369824
MICHIGAN DIABETES RESEARCH AND TRAINING CENTER
H William, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5P60DK020572-34 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: DESCRIPTION, OVERALL The Michigan Diabetes Research and Training Center (MDRTC) is a multidisciplinary unit of The University of Michigan Health System. The MDRTC is now in its thirtieth year, having been funded by the NIH/NIDDK since 1977. This application is for a seventh five-year continuation of funding for the period February 1, 2008 through January 31, 2013. The Center exists to meet the needs of investigators and thereby support and strengthen the University´s interdepartmental activities in research, training and outreach in the field of diabetes, its complications and related endocrine and metabolic disorders. The resources provided by the MDRTC have expanded and enriched the base of investigators involved in diabetes research, the Center´s most important resource, and have facilitated innovative multidisciplinary biomedical and translational research programs. The overall goals of the MDRTC are to 1. Facilitate and focus basic molecular and cellular research in the areas of diabetes, its complications and related endocrine and metabolic disorders. 2. Promote the application of relevant new knowledge to innovative, relevant, feasible, and cost-effective approaches to the prevention and control of diabetes and its complications through behavioral, clinical, epidemiologic, and health services research. 3. Evaluate, refine and disseminate new knowledge regarding diabetes, its complications, and related disorders into sustainable, widespread community practice, especially in communities at increased risk. 4. Recruit, train, motivate and retain an effective workforce of basic, clinical, epidemiologic, and health services investigators and health care providers in the areas of diabetes, endocrinology and metabolism
Keywords: Area; base; Behavioral; Biomedical Research; Clinical; Communities; Community Practice; cost effective; diabetes control; Diabetes Mellitus; Disease; Education and Outreach; Endocrine System Diseases; Endocrinology; Epidemiology; Funding; Goals; Health Personnel; Health Services; Health Services Research; Health system; innovation; Knowledge; meetings; Metabolic Diseases; Michigan; Molecular; multidisciplinary; National Institute of Diabetes and Digestive and Kidney Diseases; Prevention approach; programs; Recruitment Activity; Research; Research Personnel; Research Training; Resources; Risk; Training; Translational Research; United States National Institutes of Health; Universities
Project start date: 1996-12-01
Project end date: 2012-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: RFA-DK-06-014
5P60DK020572-34 (2011): $1775457
3P60DK020572-34S1 (2011): $400000
PATIENT NAVIGATION FOR CRC SCREENING WITH LOW-INCOME MINORITIES
H William, Professor
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 5R01CA120658-05 from National Cancer Institute
Abstract: Colorectal Cancer (CRC) incidence and mortality rates are highest in African Americans (AA´s) compared with all other ethnic groups. One factor that may contribute to this trend is the lower rate of participation in CRC screening among AAs, which is critical to the prevention and early detection of CRC. Recent data indicate that the removal of precancerous polyps (via colonoscopy) decreases CRC incidence by 75-90 percent. Despite the implementation of national policy changes to increase CRC screening (through Medicaid/Medicare reimbursement for CRC screening and easier "open" access to colonoscopy) adherence remains alarmingly low. Our preliminary data show that, even after implementation of standard patient navigation (SPN) (i.e., assisting patients with making/keeping their appointments), only 40 percent of low-income minorities followed-through on their physician recommendation. Guided by Cognitive-Behavioral Social Learning Theory as a conceptual framework and cultural targeting as an intervention strategy, the proposed randomized clinical trial will investigate integrating within SPN a targeted discussion of intrapersonal and cultural barriers to colonoscopy (i.e., fear, lack of knowledge, medical mistrust, fatalism and fear) prevalent with low-income AAs. Based on research on source credibility and reference group-based social identity theory, we will also explore navigator status as a peer on the impact of culturally targeted PN. Thus, we will compare three PN strategies SPN carried out by a professional navigator, Culturally Targeted PN carried out by a professional (CTPN-Pro) and Culturally Targeted PN carried out by a peer who has undergone colonoscopy (CTPN-Peer). Specific Aims Aim 1 Compare the efficacy of SPN, CTPN-Pro, and CTPN-Peer on adherence to colonoscopy CRC screening in average risk, low-income AAs who have a primary care physician referral for colonoscopy. Aim 2 Explore potential mechanisms (i.e., mediators) underlying the beneficial effects of CTPN-Pro and CTPN-Peer and to examine for whom the CTPN-Pro and CTPN-Peer are most effective (i.e., moderators). Aim 3 Compare the cost effectiveness of CTPN-Pro and CTPN-Peer. Cost effectiveness will be examined in terms of direct clinical costs of screening (i.e., savings associated with more efficient use of personnel, space, and equipment) and patient costs (i.e., costs of CRC treatment and the opportunity costs to the patient per life-year saved). Results from the proposed work will facilitate the broad dissemination of PN to reduce ethnic and racial health disparities in CRC incidence mortality and will advance our understanding of PN
Keywords: Address; Adherence (attribute); African American; American Cancer Society; Appointment; base; Behavior Therapy; Behavioral; cancer therapy; Clinic; Clinical; clinical practice; Cognitive; Colon; Colonoscopy; Colorectal Cancer; colorectal cancer screening; Communities; comparative efficacy; coping; cost; cost effectiveness; Data; design; Effectiveness; Ensure; Equipment; Ethnic group; evidence base; Excision; Flexible fiberoptic sigmoidoscopy; Fright; Guidelines; health disparity; Health Professional; Human Resources; improved; Incidence; Intervention; Knowledge; Life; Low income; Measures; Mediator of activation protein; Medical; Medicare/Medicaid; Methods; Minority; Modeling; Mortality Vital Statistics; novel; opportunity cost; Patients; peer; Physicians; Policies; Polypectomy; Precancerous Polyp; Prevention; Primary Care Physician; Professional Organizations; programs; public health medicine (field); racial and ethnic; Randomized Clinical Trials; Recommendation; Rectum; Research; Risk; Savings; Screening procedure; Self Efficacy; social; social cognitive theory; Social Identification; Source; System; Testing; theories; Time; Transportation; trend; Work
Project start date: 2007-09-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5R01CA120658-05 (2011): $554293
Sponsored Links Excellgen http://Excellgen.com
CELLULAR DIVERSITY AND CLINICAL RELEVANCE OF STEM CELLS IN PANCREATIC CANCER
H William, Assistant Professor
Johns Hopkins Universitycity: Baltimore country: United States (us)
Grant 1R01CA150142-01A1 from National Cancer Institute
Abstract: Cancer stem cells (CSC) have been identified in an increasing number of human malignancies, and their enhanced growth potential has suggested that they play a major role in disease initiation, maintenance, relapse and progression. We hypothesize that better understanding CSCs will ultimately improve long-term clinical outcomes and have begun to study CSC in pancreatic adenocarcinoma, a leading cause of cancer deaths. We have found that pancreatic cancer cells with increased tumorigenic potential express aldehyde dehydrogenase (ALDH), a detoxifying enzyme expressed by many normal stem cells. Moreover, ALDH+ cells express genes consistent with the epithelial-mesenchymal transition and are more invasive and migratory when compared to bulk tumor cells. We have also compared ALDH+ cells with CD44+CD24+ cells that have also been identified by others as pancreatic CSC and found that each phenotype marks distinct cell populations that are largely non- overlapping. Interestingly, each CSC population is equally capable of forming tumors, but ALDH+ cells are often more migratory and invasive. Based on these findings, we hypothesize that individual tumors contain distinct CSC populations that may or may not share specific functional properties. Moreover, these findings suggest that CSCs may vary amongst pancreatic tumors from different patients depending on their specific genetic mutations or stage of disease. Since the development of CSC targeting strategies requires their precise identification, it is imperative that the relationship between their phenotype and functional properties and the factors that influence this relationship are better understood. Moreover, it is likely that extracellular signals within the tumor microenvironment regulate CSC properties, but this is also poorly understood. We propose to address these questions and will (1) Define the relationship between distinct CSC populations in pancreatic cancer; (2) Examine the cellular diversity of pancreatic CSC; and (3) Determine whether interactions between pancreatic CSCs and the extracellular matrix can serve as novel CSC targeting strategies. Several groups have identified pancreatic cancer stem cells with the increased tumorigenic and metastatic potential. We will determine whether these cells differ amongst individual patients and regulated by the tumor environment. These findings may improve the treatment and survival of patients with pancreatic carcinoma
Keywords: Address; Adenocarcinoma Cell; aldehyde dehydrogenases; base; Cancer Etiology; Cancer stem cell; CD44 gene; Cells; Cessation of life; chemotherapeutic agent; Clinical; clinically relevant; Collagen Type I; Desmoplastic; Development; Disease; Disease Progression; Drug Metabolic Detoxication; Environment; Enzymes; Epithelial; Erinaceidae; extracellular; Extracellular Matrix; Focal Adhesion Kinase 1; gemcitabine; Gene Mutation; Genes; Genetic; Growth; Hereditary Disease; Human; improved; In Vitro; in vivo; Individual; innovation; Integrins; Laboratories; Maintenance; Malignant neoplasm of pancreas; Malignant Neoplasms; Mediating; Mesenchymal; neoplastic cell; Newly Diagnosed; Normal tissue morphology; notch protein; novel; Outcome; outcome forecast; Pancreas; Pancreatic Adenocarcinoma; pancreatic cancer cells; Pancreatic carcinoma; Pancreatic Ductal Adenocarcinoma; pancreatic neoplasm; Patients; Phenotype; Play; Population; prevent; Property; Relapse; Reporting; Resistance; Role; self-renewal; Signal Pathway; Signal Transduction; Staging; stem cell niche; stem cell population; Stem cells; Stromal Cells; success; Therapeutic; tumor; tumorigenic; Validation; Work
Relevance: Several groups have identified pancreatic cancer stem cells with the increased tumorigenic and metastatic potential. We will determine whether these cells differ amongst individual patients and regulated by the tumor environment. These findings may improve the treatment and survival of patients with pancreatic carcinoma
Project start date: 2011-09-14
Project end date: 2016-07-31
Budget start date: 14-SEP-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-10-067
1R01CA150142-01A1 (2011): $344964
TREATING CANCER-RELATED FATIGUE THROUGH SYSTEMATIC BRIGHT WHITE LIGHT
H William, Professor
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 1R21CA158954-01A1 from National Cancer Institute
Abstract: Cancer related fatigue (CRF), defined by the National Comprehensive Cancer Network as "a distressing, persistent, subjective sense of physical, emotional, and cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity," can severely interfere with activities of daily living, physical capacity, and ability to work. There are even reports of fatigue being a factor in patient requests for hastened death. CRF can represent a serious clinical problem after all treatment has ended. In our research with cancer survivors 1 to 3 years after completion of hematopoietic stem cell transplant (HSCT), 40% of those we interviewed reported that CRF was a major obstacle to the resumption of usual activities. Despite its impact on quality of life, CRF is under-reported, under-diagnosed, and under- treated. There is no widely accepted CRF intervention that has demonstrated clinical efficacy. A variety of pharmacologic agents have been studied to treat CRF; most notably psychostimulants, antidepressants, and corticosteroids. But there is not sufficient evidence to recommend the use of any of the currently available pharmacologic agents. A number of non-pharmacologic strategies have been tested. The most promising are exercise and cognitive-behavior therapy (CBT). Results from two randomized clinical trials suggest that exercise and CBT are equal in overall efficacy, but with only moderate effects. Indeed, at this time there is no "gold standard" treatment for CRF. One promising new intervention for CRF is "bright white light" (BWL --- systematic daily 30-minute exposure to bright white light from a commercially available "lightbox") treatment. In a small randomized controlled clinical trial, BWL was protective against increases in sleep disturbances, mood symptoms and fatigue across cycles of chemotherapy. We want to investigate BWL to control CRF in 1 to 3 year survivors of HSCT for three reasons. First, CRF is a major problem for a large proportion of survivors (40%). Second, BWL may be more acceptable to survivors than CBT or exercise because BWL is less physically demanding and can be carried out at home. Third, BWL is likely to be less expensive since it can be implemented by phone, requiring less professional and patient time and effort than that required for exercise and CBT. The feasibility of the proposed research is assured by the fact that we have identified a group of 150 HSCT survivors who report clinically significant levels of CRF and who have provided informed consent to participate in further research. Specific Aims 1) Develop and pilot test a BWL exposure intervention with HSCT survivors suffering from CRF to assess the impact on fatigue, sleep quality, and quality of life using objective and subjective measures; 2) To investigate the possible mediating effects of depression on fatigue; and 3) Assess the feasibility and acceptability of BWL as an intervention for CRF in cancer survivors. Cancer related fatigue (CRF) severely interferes with cancer survivors´ daily living, physical capacity, and ability to work, and can linger long after all treatment has ended. To date, CRF treatments have produced only moderate results. The proposed project will investigate the impact of systematic bright white light exposure in cancer survivors to minimize their CRF
Keywords: Activities of Daily Living; Adjustment Disorders; Adrenal Cortex Hormones; Antidepressive Agents; arm; Boxing; Cancer Burden; Cancer Control; Cancer Intervention; Cancer Patient; Cancer Survivor; cancer therapy; Cessation of life; chemotherapy; Chemotherapy-Oncologic Procedure; Clinical; clinical efficacy; clinically significant; Cognitive; Cognitive Therapy; Diagnosis; Distress; efficacy testing; Emotional; Exercise; exhaustion; Exposure to; Fatigue; Foundations; Goals; Gold; Hematopoietic stem cells; Home environment; Informed Consent; Intervention; Interview; Israel; Life; Light; light treatment; malignant breast neoplasm; Malignant Neoplasms; Measures; Mediating; Mental Depression; Moods; National Comprehensive Cancer Network; Outcome; Patients; Physical Capacity; Placebos; Procedures; psychostimulant; Quality of life; Randomized Clinical Trials; Randomized Controlled Clinical Trials; Recruitment Activity; Reporting; Research; Sleep; Sleep disturbances; standard care; standardize measure; Stem cell transplant; Survivors; Symptoms; Telephone; Testing; Time; Treatment-Related Cancer; Work
Relevance: Cancer related fatigue (CRF) severely interferes with cancer survivors´ daily living, physical capacity, and ability to work, and can linger long after all treatment has ended. To date, CRF treatments have produced only moderate results. The proposed project will investigate the impact of systematic bright white light exposure in cancer survivors to minimize their CRF
Project start date: 2011-08-01
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-09-167
1R21CA158954-01A1 (2011): $228333
MYELOMA STEM CELL TARGETING BY LIVER X RECEPTORS
H William, Assistant Professor
Johns Hopkins Universitycity: Baltimore country: United States (us)
Grant 1R21CA155733-01A1 from National Cancer Institute
Abstract: Although mature plasma cells constitute the vast majority of tumor cells and are responsible for clinical symptoms in multiple myeloma (MM), they have little to no clonogenic growth potential either in vitro or in vivo. We have recently found that clonotypic MM cells phenotypically resembling normal memory B cells are able to give rise to mature plasma cells in immunodeficient mice and propagate disease during serial transplantation. These results demonstrate that these cells are capable of both differentiation and self-renewal, suggesting that they represent the cancer stem cell (CSC) in MM. We have recently found that MM CSCs are resistant to standard chemotherapeutic agents, but can be targeted by the Hedgehog (Hh) signaling pathway that is active during normal embryonic development and in a wide variety of cancers. Several novel Hh pathway inhibitors have recently entered clinical testing, and one of these has exhibited clinical activity validating Hh signaling as a therapeutic target in human cancers. However, all of these approaches have been designed to inhibit SMOOTHEDED (SMO) a key component of the Hh signal transduction pathway, and emergence of resistance mechanisms have been reported. Therefore, novel strategies capable of inhibiting Hh signaling without directly targeting SMO are needed. Our preliminary data demonstrate that agonists of the Liver X Receptor (LXR), a nuclear hormone receptor that interacts with Hh signaling in normal cells, can attenuate Hh pathway activity in MM, reduce the frequency of MM CSC, and limit clonogenic MM growth in vitro. Therefore, we hypothesize that LXR agonists are novel anti-cancer agents that may target MM CSCs through the inhibition of Hh signaling. We propose to build on these findings and will specifically 1). Examine the effects of LXR agonists in MM and 2). Examine the interaction between the LXR and Hedgehog signaling pathways in MM. Multiple myeloma is largely an incurable disease, but we recently identified myeloma stem cells that may be responsible for disease relapse and progression. We will study whether a novel pathway regulated by the Liver X receptor can inhibit myeloma stem cells and improve clinical outcomes
Keywords: Affect; Agonist; Animals; Antineoplastic Agents; Attenuated; B-Lymphocytes; Bone Marrow; Cancer stem cell; Cell physiology; Cells; Characteristics; chemotherapeutic agent; Cholesterol; Clinical; Clonal Expansion; Data; design; Disease; Drug resistance; Embryonic Development; Erinaceidae; Exhibits; Frequencies (time pattern); Growth; hedgehog signal transduction; Human; Immunodeficient Mouse; Immunoglobulin Gene Rearrangement; improved; In Vitro; in vivo; Inflammatory; inhibitor/antagonist; Ligands; Liver; Malignant - descriptor; Malignant Neoplasms; Mediating; Memory B-Lymphocyte; Multiple Myeloma; Mutation; neoplastic cell; Normal Cell; novel; novel strategies; Nuclear Hormone Receptors; Outcome; Pathway interactions; plasma cell differentiation; Plasma Cells; Production; Property; receptor; Recurrent disease; Relapse; Reporting; research clinical testing; Resistance; resistance mechanism; Role; self-renewal; Signal Transduction Pathway; smoothened signaling pathway; Solid Neoplasm; Specimen; Stem cells; Stromal Cells; Symptoms; Therapeutic; therapeutic target; Transplantation; tumor; tumorigenic
Relevance: Multiple myeloma is largely an incurable disease, but we recently identified myeloma stem cells that may be responsible for disease relapse and progression. We will study whether a novel pathway regulated by the Liver X receptor can inhibit myeloma stem cells and improve clinical outcomes
Project start date: 2011-07-01
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-08-165
1R21CA155733-01A1 (2011): $223133
H William, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Abstract: Administration Core The Administration Core of the MCDTR provides leadership, infrastructure, and resources to ¿ Raise awareness of, and interest in, type 2 translational research in diabetes and create an environment that supports such research. ¿ Support new and established investigators engaged in research to translate interventions with proven efficacy into real worid health care settings, communities, and populations at risk. ¿ Administer Cores that provide Center members with services critical to type 2 translational research in diabetes. ¿ Provide education and training and to foster interdisciplinary collaborations. ¿ Administer the Center´s P/FS Grants Program. ¿ Maintain the Center´s website. The Administration Core is responsible for identifying and supporting researchers engaged in type 2 translational research; for developing and implementing Cores to provide services to funded T2 translational researchers locally, regionally, nationally and internationally; for overseeing the allocation of Center resources; for implementing an Enrichment Program; for implementing a process for solicitation, review selection, monitoring, and follow-up of the Center´s Pilot and Feasibility Study Grants; and for developing and maintaining a website that integrates seamlessly with the NIDDK Centers program website
Keywords: Awareness; clinical practice; Community Practice; community setting; cost effectiveness; Diabetes Mellitus; Diabetes prevention; Environment; evidence base; Feasibility Studies; follow-up; Fostering; Funding; Grant; Healthcare; Instruction; interdisciplinary collaboration; interest; Intervention; Leadership; member; Michigan; Minority Groups; Monitor; multidisciplinary; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Persons; Pilot Projects; Populations at Risk; Process; Productivity; programs; racial and ethnic; Research; Research Infrastructure; Research Personnel; Resources; Services; Training and Education; Translating; Translational Research; Ursidae Family; web site
Relevance: RELEVANCE (See instructions): The number of persons with diabetes has increased over the past decade. Racial and ethnic minority groups bear a disproportionate burden of diabetes and its complications. The MCDTR provides researchers with resources to translate evidence-based approaches to diabetes prevention and treatment into real worid clinical and community practice. The Center enhances the productivity, efficiency, cost-effectiveness, and multidisciplinary nature of type 2 translational research in diabetes
Budget start date: 6-SEP-2011
Budget end date: 30-AUG-2012
PFA/PA: RFA-DK-10-009
1P30DK092926-01_5554 (2011): $174687
CANCER STEM CELL TARGETING IN MULTIPLE MYELOMA
H William, Assistant Professor
Johns Hopkins Universitycity: Baltimore country: United States (us)
Grant 5R01CA127574-04 from National Cancer Institute
Abstract: Accumulating evidence suggest that many human cancers consist of functionally heterogeneous cells organized in a hierarchical manner with less mature cancer stem cells (CSC) giving rise to differentiated tumor cells. The distinction between these cell types has important implications for the development of effective anti- cancer strategies as mature tumor cells that form the majority of cells and phenotypically characterize the disease lack long-term replicative potential. In contrast, rare CSC appear to arise from the malignant transformation of normal stem cells or progenitors and retain the capacity to both self-renew and produce mature progeny. Therefore, CSC are thought to possess the growth potential to reform tumors that is clinically recognized as disease relapse or progression. We have studied CSC in multiple myeloma (MM), a disease characterized by the clonal expasion of neoplastic plasma cells. Although plasma cells are the hallmark of the disease, we found that these cells are terminally differentiated and have limited replicative potential. Instead, MM plasma cells arise from a self-renewing CSC compartment that phenotypically resembles normal memory B cells. Our preliminary data demonstrate that MM CSC are relatively resistant to drugs currently used to clinically treat the disease and biologically distinct from MM plasma cells; these data may explain the typical clinical response pattern of MM patients to treatment (i.e., initial response followed by relapse and disease progression). Furthermore, we have found that cellular pathways which regulate cell fate decisions in normal stem cells are similarly active in MM CSC. We hypothesize that CSC are responsible for the long-term outcomes of patients with MM and that effective stem cell targeted strategies will lead to long-term remissions. Accordingly, we propose to 1). Further characterize MM CSC and study their clinical relevance; and 2). Study the role of developmental signaling pathways in the regulation of MM CSC and their potential as therapeutic targets. We previously demonstrated that clonogenic cells in multiple myeloma are not plasma cells that are typically associated with the disease, but rather mature B cells that appear to have the capacity to undergo self-renewal and give rise to terminally differentiated tumor cells (plasma cells). We propose to further characterize myeloma stem cells by correlating their frequency and growth potential with validated prognostic factors that predict clinical outcomes as well as investigate the role of developmental signaling pathways that include Hedgehog, Notch and Wnt, in regulating myeloma cancer stem cells
Keywords: acute granulocytic leukemia; acute myeloid leukemia; acute nonlymphocytic leukemia; AML - Acute Myeloid Leukemia; base; Biological; Blood Plasma Cell; Brill-Symmers Disease; Cancer stem cell; Cancer, Oncology; Cancers; cell type; Cells; Clinical; clinical relevance; clinical significance; Clinical Treatment; clinically relevant; clinically significant; Data; Development; Disease; Disease Progression; Disease remission; disease/disorder; Disorder; Drug resistance; drug resistant; drug sensitivity; Erinaceidae; failure; Failure (biologic function); FLR; Follicle Center Lymphoma; Follicular Lymphoma; Follicular Non-Hodgkin`s Lymphoma; Frequencies (time pattern); Frequency; General Prognostic Factor; Generalized Growth; Growth; Health; heavy metal lead; heavy metal Pb; Hedgehog (Hh) signal transduction pathway; hedgehog signaling pathway; Hedgehogs; Hematologic Cancer; Hematologic Malignancies; Hematologic Neoplasms; Hematological Malignancies; Hematological Neoplasms; Hematological Tumor; Hematopoietic Cancer; hh signaling pathway; Human; Human, General; In Vitro; in vivo; Lead; Leukemia, Myelocytic, Acute; Lymphoma, Follicular; Lymphoma, Giant Follicular; Lymphoma, Nodular; Maintenance; Maintenances; malignancy; Malignant; Malignant - descriptor; Malignant Hematologic Neoplasm; Malignant Neoplasms; Malignant Tumor; Man (Taxonomy); Man, Modern; Mature B-Cell; Mature B-Lymphocyte; Memory B Cell; Memory B-Lymphocyte; Mother Cells; Multiple Myeloma; Myeloblastic Leukemia, Acute; Myelogenous Leukemia, Acute; myeloma; Myeloma, Plasma-Cell; myelomatosis; neoplasm/cancer; neoplastic cell; Neoplastic Plasma Cell; Newly Diagnosed; notch; notch protein; notch receptors; novel; oncology; ontogeny; Outcome; pathway; Pathway interactions; Patients; Pattern; Pb element; Plasma Cells; Plasmacytes; plasmocyte; Population; Production; progenitor; Progenitor Cells; Prognostic Factor; Prognostic/Survival Factor; Property; Property, LOINC Axis 2; Recurrent disease; Regulation; Relapse; Relapsed Disease; Remission; Research Specimen; Resistance; resistance to Drug; resistant; resistant to Drug; response; RMSN; Role; self-renewal; Signal Pathway; smoothened signaling pathway; social role; Specimen; stem; stem cell fate; Stem cells; therapeutic target; Tissue Growth; trial regimen; trial treatment; tumor; Tumor Cell
Project start date: 2008-04-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-070
5R01CA127574-04 (2011): $263243
REL B MEDIATED-REDOX REGULATION OF RADIATION THERAPY
H William, Assistant Professor
University Of Kentuckycity: Lexington country: United States (us)
Grant 1R01CA143428-01A1 from National Cancer Institute
Abstract: Accumulating data suggest that prostate cancers exist in an elevated state of oxidative stress and that reactive oxygen species (ROS) contribute importantly to the cytotoxic effect of ionizing radiation (IR). However, ROS also participate in cellular signaling processes leading to adaptive responses that reduce the effectiveness of radiation therapy. Thus, despite rapid advances in treatment techniques, the outcome of radiation therapy, especially for patients with tumors with unfavorable prognoses remains to be improved. The goal of this project is to identify novel mechanisms that could lead to the development of specific measures for effective treatment of aggressive prostate cancers. We have identified the alternative pathway of the redox sensitive nuclear factor kappa beta (NF-?B) as a major contributor to prostate cancer growth and progression. Preliminary data indicate that 1) aggressive prostate cancers have high nuclear RelB, a member of the alternative pathway of NF-B and manganese superoxide dismutase (MnSOD), a critical antioxidant enzyme levels; 2) suppression of RelB in androgen independent-aggressive prostate cancer cells results in reduction of interleukin 8 (IL8) levels in tumor cells and reduced tumor growth in vivo; 3) overexpression of RelB in androgen responsive prostate cancer cells results in enhanced tumor growth and production of IL8 but reduced prostate specific androgen (PSA) production; and 4) suppression of RelB nuclear translocation enhances radiation sensitivity of prostate cancer. Based on these novel and important preliminary findings, we hypothesize that RelB regulates prostate cancer response to radiation via a MnSOD dependent, NF-?B switch to activate expression of IL8 and suppress expression of PSA in prostate cancer cells. We propose that clinical testing for recurrent tumor growth should involve measuring levels of IL8 in addition to employing the standard PSA test. Combining these tests will enhance accurate cancer detection and prognosis. To test this hypothesis and validate the proof-of-concept for the combined use of IL8 and PSA as prognostic factors, three interrelated specific aims will be addressed. Aim 1 will elucidate the mechanism by which MnSOD modulates the effect of RelB on the transcription of IL8 and PSA in prostate cancer cells using biochemical and molecular biology approaches. Aim 2 will examine the role of IL8 in the protection against the effects of radiation therapy of prostate cancer. Aim 3 will determine whether serum IL8 level is a predictive marker of prostate cancer response to radiation therapy using samples from cancer patients. These mechanistic based, bench to bedside approaches should provide novel insights into the mechanisms of prostate cancer resistant to radiation therapy and may provide practical predictive measures for prostate cancer diagnostic, treatment planning and surveillance. Prostate cancer is the most frequently diagnosed cancer in men and the number of men who die from prostate cancer is unacceptably high. The results obtained from this study will provide insights into the novel mechanisms by which interleukin 8 (IL8) and prostate specific antigen (PSA) are differentially regulated and will test a proof-of-concept for using their relationship to predict the efficacy of radiation therapy for treating prostate cancer. Thus, this study will enable physicians to tailor risk-adjusted strategies for treatment of prostate cancer
Keywords: Active Follow-up; Active Oxygen; Address; Affinity Chromatography; affinity purification; Androgenic Agents; Androgenic Compounds; Androgens; Animal Model; Animal Models and Related Studies; Anionic Neutrophil-Activating Peptide; anti-oxidant; Antioxidants; Assay; base; Basic Research; Basic Science; bench bed side; bench bedside; bench to bed side; bench to bedside; Binding; Binding (Molecular Function); Bioassay; Biochemical; Biologic Assays; Biological Assay; Blood Serum; Cancer Cause; cancer cell; Cancer Center; Cancer Detection; cancer diagnosis; Cancer Diagnostics; Cancer Etiology; Cancer of Prostate; Cancer Patient; Cancer Prognosis; Cancer Radiotherapy; Cancer Staging; cancer type; Cancers; Cessation of life; Chemotactic Factor, Macrophage-Derived; Chemotactic Factor, Neutrophil; Chemotactic Factor, Neutrophil, Monocyte-Derived; Chromatography, Affinity; Clinical; Clinical Evaluation; Clinical Research; Clinical Study; clinical test; Clinical Testing; computerized data processing; Cultured Cells; cytotoxic; cytotoxicity; Data; data processing; Death; Development; Diagnosis; Diagnostic Neoplasm Staging; DNA Molecular Biology; EC 3.4.21.34; effective therapy; Effectiveness; Electromagnetic Radiation, Ionizing; Enzymes; experiment; experimental research; experimental study; Family; Fletcher Factor; follow-up; Forecast of outcome; gamma-Seminoprotein; GCP-IL-8; Gene Expression; Gene Transcription; General Prognostic Factor; Generalized Growth; Genes; Genetic Transcription; Genital System, Male, Prostate; Goals; Granulocyte Chemotactic Peptide-Interleukin-8; Growth; heavy metal lead; heavy metal Pb; hK3 Kallikrein; Human; Human Prostate; Human Prostate Gland; Human, General; Immune Precipitation; Immunoglobulin Enhancer-Binding Protein; Immunoprecipitation; improved; in vivo; inflammatory marker; insight; Interleukin-8; Ionizing radiation; irradiation; Kallikrein 3; kappa B Enhancer Binding Protein; Kentucky; kininogenin; KLK3; language translation; Lead; Leukocyte Adhesion Inhibitor; Link; Lytotoxicity; malignancy; Malignant Cell; Malignant neoplasm of prostate; Malignant Neoplasms; Malignant prostatic tumor; Malignant Tumor; Malignant Tumor of the Prostate; Man (Taxonomy); Man, Modern; Manganese Superoxide Dismutase; Measures; Mediating; member; men; men`s; Methods and Techniques; Methods, Other; Mn Superoxide Dismutase; Mn-SOD; model organism; Modeling; Molecular Biology; Molecular Interaction; Mutagenesis, Site-Directed; neoplasm recurrence; Neoplasm Staging; neoplasm/cancer; neoplastic cell; Neutrophil Activating Peptide; Neutrophil Activation Factor; Neutrophil Activation Peptide; Neutrophil-Activating Peptide, Lymphocyte-Derived; Neutrophil-Activating Peptide, Monocyte-Derived; NF-kappa B; NF-kappaB; NF-kB; NFKB; novel; Nuclear; Nuclear Factor kappa B; nuclear factor kappa beta; Nuclear Transcription Factor NF-kB; Nuclear Translocation; ontogeny; Outcome; outcome forecast; overexpression; oxidation reduction reaction; Oxidation-Reduction; Oxidative Stress; Oxygen Radicals; P-30 Antigen; pathway; Pathway interactions; Patients; Pb element; Physicians; Plasma Kallikrein Precursor; Plasma Prekallikrein; Play; Predictive Factor; Pro-Oxidants; Production; Prognosis; Prognostic Factor; Prognostic/Survival Factor; Prostate; Prostate CA; Prostate Cancer; Prostate Gland; Prostate Specific Antigen Preproprotein; Prostate-Specific Antigen; Prostatic Cancer; Prostatic Gland; Proteomics; public health relevance; Radiation; Radiation Sensitivity; Radiation therapy; Radiation Tolerance; Radiation-Ionizing Total; Radiosensitivity; Radiotherapeutics; Radiotherapy; ray (radiation); Reactive Oxygen Species; Recurrent Neoplasm; Recurrent tumor; Redox; Regulation; research clinical testing; research study; Resistance; resistant; response; Risk; RNA Expression; RNA, Small Interfering; Role; Sampling; Semenogelase; Seminin; Serum; signal processing; siRNA; Site-Directed Mutagenesis; Site-Specific Mutagenesis; Small Interfering RNA; social role; Targeted DNA Modification; Targeted Modification; Techniques; Testing; Therapeutic Androgen; Time; Tissue Growth; Transcription; Transcription Factor NF-kB; Transcription Regulation; Transcription, Genetic; Transcriptional Control; Transcriptional Regulation; Translating; Translatings; treatment planning; treatment strategy; tumor; Tumor Cell; tumor growth; Tumor Staging; Tumorigenicity; Universities; Visit
Relevance: Prostate cancer is the most frequently diagnosed cancer in men and the number of men who die from prostate cancer is unacceptably high. The results obtained from this study will provide insights into the novel mechanisms by which interleukin 8 (IL8) and prostate specific antigen (PSA) are differentially regulated and will test a proof-of-concept for using their relationship to predict the efficacy of radiation therapy for treating prostate cancer. Thus, this study will enable physicians to tailor risk-adjusted strategies for treatment of prostate cancer
Project start date: 2011-01-01
Project end date: 2015-11-30
Budget start date: 1-JAN-2011
Budget end date: 30-NOV-2011
PFA/PA: PA-10-067
1R01CA143428-01A1 (2011): $401390
ESTROGENS, OVARIAN AGING AND CALCIUM CHANNEL MODULATION
H William
Texas A&m University Health Science Ctrcity: College Station country: United States (us)
Grant 1R01AG041360-01 from National Institute On Aging
Keywords: Adult; Age-associated memory impairment; Aging; basal forebrain cholinergic neurons; Behavioral; Biological; Calcium Channel; Cognitive; cognitive function; Controlled Environment; Dementia; Estrogen Therapy; Estrogens; Female; Future; G-Protein-Coupled Receptors; Genomics; Goals; Health Care Costs; Image; Impaired cognition; Inbred F344 Rats; Incidence; Individual; Instruction; Menopause; MicroRNAs; Modeling; Molecular; neuronal excitability; Neurons; non-genomic; Operative Surgical Procedures; Ovarian; Pharmacotherapy; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiology; Play; Postmenopause; postsynaptic; presynaptic; Rattus; research study; restoration; Risk; Role; Running; senescence; Signal Transduction; Site; stroke; synaptic function; Testing; Water; Western Blotting; Woman
Relevance: RELEVANCE (Seo instructions): , Clinically, it has been shown that estrogen therapy given to post-menopausal women, paradoxically increases the risk of probable dementia and impairs global Cognitive function; The ensuing annual health care costs run into the billions of dollars. We believe that the rapid (non-genomic) actions of estrogens contribute to these effects and are potential sites for drug therapies to treat post-mendpausal women
Project start date: 2011-04-15
Project end date: 2016-03-31
Budget start date: 15-APR-2011
Budget end date: 31-MAR-2012
1R01AG041360-01 (2011): $289232