ATTENUATED RHCMV DELTA 10 SIV ORAL VACCINE VECTORS ENCODING TLR5 LIGAND SEQUENCES
A Peter
University Of California Daviscity: Davis country: United States (us)
Grant 5R01DE021273-02 from National Institute Of Dental & Craniofacial Research
Keywords: Adjuvant; Agonist; Antibody Formation; Antigen Presentation; Antigens; Attenuated; base; Capsid; Capsid Proteins; Cell Maturation; Cells; Chimeric Proteins; Code; Cytomegalovirus; Cytomegalovirus Vaccines; Data; Dendritic cell activation; Dendritic Cells; Engineering; Epithelium; Female; Flagellin; Future; Generations; Genes; Heterophile Antigens; HIV; HIV vaccine; HIV-1; Human; IL10 gene; Immune; Immune response; Immune system; Immunity; Immunization; immunogenicity; improved; In Vitro; in vivo; Infection; Inflammation; Interleukin-10; Investigation; Laboratories; Length; Ligands; Lymphoid Tissue; M cell; Macaca mulatta; Modeling; Mucosal Immune Responses; mucosal site; mucosal vaccine; Mucous Membrane; mutant; Nature; nonhuman primate; novel; novel vaccines; Oral; Oral cavity; Oral mucous membrane structure; oral vaccine; Pathogenicity; peripheral blood; public health relevance; receptor; Recombinants; response; Route; Safety; Salmonella enterica; Serum; Site; SIV; System; Target Populations; Testing; Tissues; TLR2 gene; TLR5 gene; Toll-Like Receptor 5; Toll-like receptors; transmission process; Vaccine Antigen; Vaccine Design; vaccine development; vaccine efficacy; Vaccines; Vagina; vector; vector vaccine; Viral; Viral Vaccines; Viral Vector; Work
Relevance: Studies proposed in this application will provide a first investigation of a novel HIV-1 vaccine approach that incorporates a new viral vaccine vector, attenuated RhCMV¿IL10 that incorporates bacterial flagellin, a TLR5 agonist, as an adjuvant by generation and delivery of chimeric vaccine immunogens encoding flagellin sequences. Importantly, these studies will examine and develop a novel vaccine approach that is not previously tested in the SIVmac vaccine model, and carries the potential to significantly impact HIV vaccine design
Project start date: 2010-12-01
Project end date: 2015-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R01DE021273-02 (2012): $616708
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to A Peter
PROTECTIVE EFFECTS OF ANTI-C5A IN SEPSIS
A Peter
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5R01GM061656-10 from National Institute Of General Medical Sciences
Abstract: We will continue our studies to define molecular mechanisms related to development of septic cardiomyopathy in rodents after cecal ligation and puncture (CLP), with an emphasis on the roles of C5a anaphylatoxin and its receptors, C5aR and C5L2. Aim 1 will define the requirements for C3, C5, C5a receptors (C5aR, C5L2) and IL-17 for spontaneous release of cardiosuppressive cytokines (IL-12, TNF1, IL-6) from sham and CLP cardiomyocytes (CMs). These data will be compared to the presence of cytokines in heart homogenates and plasma from CLP mice. Aim 2 will determine the time course after CLP for upregulation of receptors for C5a and the cardiosuppressive cytokines (IL-12, TNF1 and IL-6) on CMs. Aim 3 will assess electrophysiological responses (action potentials, Ca2+ transients, and K+ and Ca2+ currents) as well as functional responses (by measuring intracellular calcium transients and myocyte contraction) in CMs obtained from sham and CLP rodents as a function of time after CLP. In addition, sham and CLP CMs will be studied for changes in electrophysiological and contractile responses after in vitro exposure to C5a in an effort to define molecular mechanisms by which C5a causes contractile dysfunction in CMs. Aim 4 will assess the ability of C5a to induce changes in CMs (as described in Aim 3), using sham and CLP CMs to which varying concentrations of C5a or cardiosuppressive cytokines, or both, have been added. We will determine if there is a synergy in development of electrophysiological dysfunction with combination of C5a and cardiosuppressive cytokines. Aim 5 will employ non-invasive echocardiography approaches to assess systolic and diastolic function and systemic vascular resistance, as well as other parameters, in CLP mice as compared to sham mice. We will attempt to define the roles of C3, C5, C5a and IL-17 receptors in CM dysfunction. These studies will also feature CLP mice that have been treated with neutralizing antibodies to C5a or IL-17. A C5aR knockout mouse model will also be utilized to define the role of the C5a signaling pathways in the pathogenesis of septic cardiomyopathy. Collectively, these studies should define the roles of C5a and its receptors as well as cardiosuppressive cytokines in the development of septic cardiomyopathy and how this complication can be averted or treated. Sepsis continues to be a daunting problem in humans with a single FDA approved intervention. Depending on location and clinical details, the mortality rate may be as high as 50-60%, an especially alarming statistic in view of 600,000 or more patients with sepsis in North America each year. It is clear that we have incomplete understanding of sepsis. Until this obstacle is resolved through an understanding of the molecular determinants of sepsis, treatment will be supportive and extremely costly
Keywords: Action Potentials; Affect; Anaphylatoxins; Animals; Antibodies; Appearance; base; C5a anaphylatoxin receptor; Calcium; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiomyopathies; Cardiovascular system; Characteristics; chemokine; Clinical; Complement 5a; Complication; Coupling; cytokine; Data; Defect; Development; Dose; Echocardiography; Exposure to; Failure (biologic function); FDA approved; Functional disorder; Generic Drugs; Heart; Heart failure; Human; In Vitro; in vivo; Individual; Interleukin-12; Interleukin-17; Interleukin-6; Intervention; Knockout Mice; Ligation; Literature; Location; Measures; Mediator of activation protein; Molecular; Mortality Vital Statistics; mouse model; Mus; Muscle Cells; neutralizing antibody; North America; Organ failure; Pathogenesis; Patients; Performance; Peripheral Resistance; Plasma; protective effect; public health relevance; Puncture procedure; receptor; receptor upregulation; response; Rodent; Role; Sepsis; septic; Septic Shock; Signal Pathway; statistics; Stroke Volume; Time; TNF gene; Ventricular
Relevance: Relevance Sepsis continues to be a daunting problem in humans with a single FDA approved intervention. Depending on location and clinical details, the mortality rate may be as high as 50-60%, an especially alarming statistic in view of 600,000 or more patients with sepsis in North America each year. It is clear that we have incomplete understanding of sepsis. Until this obstacle is resolved through an understanding of the molecular determinants of sepsis, treatment will be supportive and extremely costly
Project start date: 2000-09-01
Project end date: 2014-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-07-070
5R01GM061656-10 (2011): $309438
ROLE OF MACROPHAGE REGULATORY CELLS (MAC-REGS) IN IMMUNE REGULATION
A Peter
Mayo Clinic Arizonacity: Scottsdale country: United States (us)
Grant 1R01AI089846-01A1 from National Institute Of Allergy And Infectious Diseases
Abstract: We have identified a new population of CD11b+F4/80+CD68+ (macrophages) that express Foxp3. Our initial results indicate that these cells were observed in spleen, lymph nodes, bone marrow, thymus, peripheral blood, liver and other tissues. We devised a strategy to highly purify CD11b+F4/80+Foxp3+ macrophages using the Foxp3-GFP mice. Our results show that CD11b+F4/80+ macrophages expressing Foxp3 inhibited the proliferation of T cells whereas Foxp3neg macrophages did not. Foxp3pos macrophages inhibited the proliferation of T cells through cell cell contact mechanisms or soluble factors. Ablation of Foxp3 expression on CD11b+F4/80+Foxp3+ cells results in their lost capacity to inhibit the proliferation of T cells confirming that Foxp3 is directly responsible for conferring suppressive capabilities to this subpopulation of macrophages. The cytokine and genomic profiles of Foxp3pos and Foxp3neg macrophages were distinctive indicating that these cells have different biological functions. Furthermore, Foxp3pos macrophages induce de novo conversion Tregs, in contrast Foxp3neg macrophages did not. Functional analysis indicated that CD11b+F4/80+Foxp3+ macrophages are important for tolerance induction and are involved as well in tumor promotion and progression. For the first time, these studies demonstrate the existence of a distinct subpopulation of naturally occurring macrophage regulatory cells (Mac-regs) in which their suppressive function is directly correlated to the expression of Foxp3. Taken together our preliminary results lead to hypothesize that CD11b+F4/80+Foxp3+ cells (Mac-regs) subpopulation is an important subset of regulatory cells critical in the homeostatic balance of the immune system regulating immune responses which contribute to T cell tolerance induction and tumor promotion/growth. In order to test our hypothesis the following specific aims will be addressed Aim 1 will define the mechanisms by which Mac-regs inhibit other cells; Aim 2 will evaluate the mechanism of tolerance induction by Mac-regs; and Aim 3 will evaluate the role of Mac-regs in tumor promotion and growth. For the first time we have identified a population of macrophages that express Foxp3. The Foxp3+ MX are able to inhibit the effector function of T cells. In vivo biological functions of Foxp3+ MX indicate that these induce immune tolerance and are important in promoting tumor growth. These results indicate that Foxp3+ MX are an important subset of regulatory cells critical in the homeostatic balance of the immune system. Learning more about the behavior of Foxp3+ MX is critical to understand the pathological function of these cells which could be related to tolerance, autoimmunity, tumor immunity, organ transplantation, allergy, and microbial immunity
Keywords: Ablation; Address; Animals; Autoimmunity; base; Behavior; Biological; Biological Process; Bone Marrow; Cell physiology; Cells; cytokine; Data; design; Development; Disease; Equilibrium; Genomics; Goals; Growth; Hypersensitivity; Immune; Immune response; Immune system; Immune Tolerance; Immunity; in vivo; insight; ITGAM gene; Lead; Learning; Liver; lymph nodes; macrophage; Mediating; Metastatic Lesion; microbial; Mus; neoplastic cell; oral tolerance; Organ Transplantation; peripheral blood; Population; prevent; Primary Neoplasm; Regulation; Role; Spleen; Staging; T-Cell Proliferation; T-Lymphocyte; Testing; Thymus Gland; Time; Time Study; Tissues; tumor; tumor growth; Tumor Immunity; tumor progression; Tumor Promotion
Relevance: For the first time we have identified a population of macrophages that express Foxp3. The Foxp3+ MX are able to inhibit the effector function of T cells. In vivo biological functions of Foxp3+ MX indicate that these induce immune tolerance and are important in promoting tumor growth. These results indicate that Foxp3+ MX are an important subset of regulatory cells critical in the homeostatic balance of the immune system. Learning more about the behavior of Foxp3+ MX is critical to understand the pathological function of these cells which could be related to tolerance, autoimmunity, tumor immunity, organ transplantation, allergy, and microbial immunity
Project start date: 2011-08-01
Project end date: 2015-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-10-067
1R01AI089846-01A1 (2011): $375834
TARGETING SURVIVAL FACTORS FOR OCULAR NEOVASCULARIZATION
A Peter, Professor Of Ophthalmology And Neuroscie
Johns Hopkins Universitycity: Baltimore country: United States (us)
Grant 5R01EY012609-12 from National Eye Institute
Abstract: Vascular endothelial cells participating in neovascularization (NV) depend upon survival factors. If the survival factors are withdrawn or blocked, the endothelial cells undergo apoptosis and the NV regresses. Thus, identifying survival factors and finding ways to block them is a useful strategy for development of treatments for established NV. Right after sprouting, most types of NV tend to be very dependent upon vascular endothelial growth factor (VEGF) for survival, but over time the vessels mature and as part of the maturation process they acquire additional survival signals from extracellular matrix (ECM) and perivascular cells (pericytes). Defining these survival signals is an important goal. Two candidates are angiopoietin 1 (Ang1) acting through the Tie receptors on endothelial cells and platelet-derived growth factor-B (PDGF-B) acting through PDGF beta receptors on pericytes. Completely mature vessels tend to be less dependent upon VEGF, Ang1, and PDGF-B than new vessels, but this is a relative difference. For instance some normal vascular beds in adults, usually those that contain fenestrated vessels, still contain vessels that regress when VEGF is blocked. Also, while these molecules primarily target vascular cells they may also have survival-promoting effects for some neurons. Therefore, in order to target these survival signals to develop treatments for ocular NV, it is critical to determine the effect of blocking them on the normal retina and choroid as well as on ocular NV. We propose to do this using transgenic mice with inducible expression of potent blockers for each of the survival signals; soluble VEGF receptor 1 coupled to IgG Fc (VEGFtrap) to block VEGF, Ang2 to block Ang1, and soluble PDGF beta receptor coupled to IgG Fc (PDGFtrap) to block PDGF-B. The effect of expressing each of these antagonists alone and together will be examined both on choroidal NV that has been present for various amounts of time, and on the normal retina and choroid. Macrophages are another rich source of both survival and death signals for NV; therefore, we will use mice in which macrophages are ablated to determine their role in formation and regression of VEGF-induced ocular NV. This study addresses important public health problems, because it could lead to new treatments for established ocular NV which occurs in age-related macular degeneration and diabetic retinopathy, the most common causes of severe vision loss in the US
Keywords: Ablation; Acute; Address; Adult; Age; Age related macular degeneration; Angiopoietin-1; Angiopoietin-2; Apoptosis; Area; base; Benefits and Risks; Blindness; Blood Vessels; Bruch`s basal membrane structure; Cell Proliferation; Cells; Cessation of life; Chemotactic Factors; Chimeric Proteins; Choroid; Choroidal Neovascularization; Chronic; Clinical Trials; Combined Modality Therapy; Coupled; CXCR4 Receptors; Development; Diabetic Retinopathy; EGF gene; Endothelial Cells; Extracellular Matrix; Extravasation; Family member; Fc Immunoglobulins; Goals; Grant; Immunoglobulin G; Immunohistochemistry; Infiltration; ITGAM gene; Laboratories; Lead; Long-Term Effects; macrophage; Molecular; monocyte; Mononuclear; Mus; Myeloid Cells; neovascularization; Neurons; new therapeutic target; ocular neovascularization; Patients; Pericytes; Photoreceptors; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor beta Receptor; Platelet-Derived Growth Factor Receptor; Play; Process; programs; Proto-Oncogene Proteins c-sis; public health medicine (field); receptor; receptor coupling; Regimen; Relative (related person); Research Personnel; Retina; retina blood vessel structure; Retinal; Retinal Diseases; Retinal Neovascularization; retinal neuron; Reverse Transcriptase Polymerase Chain Reaction; Role; Rupture; Signal Pathway; Signal Transduction; Site; Source; Stimulus; Stromal Cell-Derived Factor 1; Structure; Structure of retinal pigment epithelium; Testing; Tetanus Helper Peptide; Therapeutic; therapeutic target; therapy development; Time; Tissues; Transgenic Mice; vascular bed; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vascular Permeabilities; WNT Signaling Pathway
Project start date: 1999-01-01
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5R01EY012609-12 (2011): $354600
CASE-PNG GLOBAL INFECTIOUS DISEASE RESEARCH TRAINING PROGRAM (D43)
A Peter, Associate Professor
Case Western Reserve Universitycity: Cleveland country: United States (us)
Grant 2D43TW007377-06 from Fogarty International Center
Abstract: Today in Papua New Guinea (PNG) infectious diseases impose a significant impact on public health. Malaria and pneumococcal pneumonia rank among the top 3 causes of out-patient visits to health centers, hospital admissions and death. Support for assistance to control and reduce the burden of infectious diseases has come through programs purchasing resources (e.g. anti-microbial drugs, insecticide-treated bed nets, vaccines). However, gaps identified through experiences of the 2005- 2010 Case-PNG Global Infectious Disease Research Training Program (GIDRTP) make clear that the PNG National Department of Health, the University of PNG and the PNG Institute of Medical Research still lack important human resources needed to conduct and sustain scientific research that will evaluate whether donated resources have been used effectively. Specifically, there are no professional PNG biostatisticians or epidemiologists at the National Department of Health, UPNG (includes the School of Medicine), or PNGIMR. Also, it is not currently possible to initiate graduate level programs in entomology in PNG because there are no professional PNG entomologists. Progress toward addressing these gaps has been accomplished during 2005-2010 Case-PNG GIDRTP. A cadre of 23 Bachelor of Science (BSc) honors students will have graduated from the University of PNG by April 2011; 18 have already completed all of their requirements. Evidence that these graduates are eager to advance their careers in infectious disease research has been demonstrated as 8 of these BSc honors graduates have secured funding to pursue Masters Degrees in Europe, Japan, Australia and the United States. Two have been awarded prestigious Fulbright International Scholar awards, and are enrolled in Masters Degree programs at Case Western Reserve University. This Case-PNG GIDRTP renewal proposal seeks to continue progress toward closing the important gaps that limit (a) instruction in math and science, (b) application of skills required for data management and analysis, and (c) development of infectious disease research expertise. Specific Aims to address these gaps are as follows. Aim 1-Sustain and expand ID research training opportunities for PNG undergraduate honors students to maintain the established ´feeder´ program that is now preparing students for graduate degree work in ID research. Aim 2-Advance ID research training opportunities for PNG students through Masters Degree programs in Public Health and Biology (CWRU) and Entomology (Michigan State University). Aim 3-Provide opportunities for PNG trainees and faculty to communicate research findings through writing s and manuscripts, developing posters and oral presentations. Aim 4-Prepare PNG scientists to become familiar with the process of writing and submitting grants to raise independent support for research projects and ID research programs. Infectious diseases impose a significant burden on the public health system in Papua New Guinea. Public health practice and scientific research on infectious diseases relevant to Papua New Guineans lags because of insufficient training and expertise in Epidemiology/Biostatistics and Entomology. This GIDRTP addresses these needs through linkage of the PNG Institute of Medical Research and academic partners with graduate degree programs at Case Western Reserve University and Michigan State University
Keywords: ing; Address; Admission activity; antimicrobial drug; Australia; Award; Beds; Biology; career; Cessation of life; Communicable Diseases; Data Analyses; data management; Development; Enrollment; Entomology; Epidemiologist; Europe; experience; Faculty; Funding; graduate student; Grant; Health; Hospitals; Human Resources; Infectious Diseases Research; Insecticides; Institutes; Instruction; International; Japan; Malaria; Manuscripts; Master`s Degree; Medical Research; medical schools; Michigan; Oral; Outpatients; Papua New Guinea; Pneumococcal Pneumonia; posters; Process; programs; public health medicine (field); Research; Research Project Grants; Research Training; Resources; Science; Scientist; Secure; skills; Students; Training Programs; United States; Universities; Vaccines; Visit; Work; Writing
Relevance: Infectious diseases impose a significant burden on the public health system in Papua New Guinea. Public health practice and scientific research on infectious diseases relevant to Papua New Guineans lags because of insufficient training and expertise in Epidemiology/Biostatistics and Entomology. This GIDRTP addresses these needs through linkage of the PNG Institute of Medical Research and academic partners with graduate degree programs at Case Western Reserve University and Michigan State University
Project start date: 2005-07-26
Project end date: 2016-07-30
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PAR-10-260
2D43TW007377-06 (2011): $270708
WHOLE GENOME SEQUENCING OF MALAGASY DUFFY-INDEPENDENT P. VIVAX
A Peter, Associate Professor
Case Western Reserve Universitycity: Cleveland country: United States (us)
Grant 1R21AI093922-01 from National Institute Of Allergy And Infectious Diseases
Abstract: Today 2.6 billion people live in areas of risk for Plasmodium vivax transmission; 106 - 313 million cases of vivax malaria annually. While Duffy blood group negativity has been considered to confer resistance to vivax malaria, our recent findings indicate that P. vivax has gained the capacity to infect erythrocytes and cause disease in Duffy-negative (Duffy(-)) people in Madagascar and suggests that P. vivax has acquire new erythrocyte infection mechanisms. In surveys of school-aged children 8.8% of asymptomatic Duffy(-) children (42/476) were P. vivax PCR-positive. Additionally, during surveys to assess in vivo efficacy of drugs recommended by the Madagascar Ministry of Health to treat malarial illness, we identified nine Duffy(-) people who had mono-infection P. vivax malaria (4.9% of 183 participants). We validated this unusual finding by microscopy to provide the first evidence for blood- stage development of P. vivax, including sexual-stage gametocytes necessary to continue the parasite lifecycle through mosquito transmission. Finally, flow cytometric analysis of erythrocytes from Malagasy study participants (n=43; many of whom experienced clinical P. vivax malaria) showed that Duffy(-) genotype and phenotype were 100% concordant, to indicate that the Duffy antigen was not cryptically expressed on the erythrocyte surface in genotypically Duffy(-) individuals. To begin understanding how P. vivax has gained capacity to infect Duffy(-) erythrocytes we propose to analyze the genome sequence of several P. vivax isolates extracted from blood samples of Duffy(+) and Duffy(-) Malagasy individuals, and the resulting data will allow us to address the following Specific Aims. Aim 1 Determine whether the same strains of P. vivax are responsible for infections of Duffy(-) and Duffy(+) individuals in Madagascar and reconstruct the population history of Malagasy P. vivax. Aim 2 Identify genes under recent positive selection in Malagasy P. vivax genomes. Our study of genetic diversity among multiple Malagasy P. vivax isolates by whole genome sequencing will allow us to determine how, or if the parasite population has partitioned in response to the important barrier imposed by Duffy negativity. By identifying loci under recent positive selection, our studies have strong potential to identify new parasite invasion ligands contributing to Duffy-independent erythrocyte invasion. - Today 2.6 billion people live in areas of risk for Plasmodium vivax (Pv) transmission; 106 - 313 million cases of vivax malaria annually. Duffy blood group negativity has been considered to confer resistance to vivax malaria, however, our recent findings indicate that Pv has gained the capacity to infect erythrocytes and cause disease in Duffy-negative people in Madagascar, suggests that Pv has acquire new erythrocyte infection mechanisms. Through whole genome sequence analysis we will reveal differences between Pv strains infecting Duffy-negative vs. Duffy-positive people that will help identify genes evolving to expand the erythrocyte invasion capacity of Pv
Keywords: 0-11 years old; Address; Admixture; African; Age; Alleles; allelic variant; Allelomorphs; Antigens; Area; ATGN; base; Binding Proteins; Blood; blood corpuscles; Blood erythrocyte; Blood Grouping; Blood groups; Blood normocyte; Blood reticulocyte; Blood Sample; Blood specimen; Blood typing procedure; Candidate Disease Gene; Candidate Gene; Characteristics; Child; Child Youth; children; Children (0-21); Clinical; Culicidae; Data; Deoxyribonucleic Acid; Development; Diffusely basophilic erythrocyte; Disease; disease/disorder; Disorder; DNA; drug efficacy; Epidemiology; Erythrocytes; Erythrocytic; experience; Frequencies (time pattern); Frequency; gene product; Gene variant; Genes; Genetic Diversity; Genetic Polymorphism; Genetic Variation; Genome; genome sequencing; Genotype; Health; History; Human; Human, Child; Human, General; immunogen; in vivo; Individual; Infection; Invaded; Laboratories; Life; Ligand Binding Protein; Ligands; Linkage Disequilibrium; Linkage Disequilibriums; Madagascar; Malagasy Republic; Malaria; Malaria, Vivax; Man (Taxonomy); Man, Modern; Marrow erythrocyte; Marrow reticulocyte; Measures; Meiotic Recombination; Microscopy; Molecular Evolution; Mono-S; MonoS; Mosquitoes; Paludism; parasite invasion; Parasites; Participant; Phenotype; Plasmodium Infections; Plasmodium vivax; Plasmodium vivax Malaria; Polychromatophilic Erythrocyte; polymorphism; Polymorphism (Genetics); Polymorphism, Genetic; Population; Population Sizes; Pressure; pressure; Pressure- physical agent; Prevalence; Proteins; public health relevance; Recording of previous events; Red Blood Cells; Red blood corpuscule; Red Cell; Red cell of marrow; Relaxation; Research; Resistance; resistant; response; Reticulocytes; Reticuloendothelial System, Blood; Reticuloendothelial System, Erythrocytes; Risk; school age; School-Age Population; SEQ-AN; Sequence Analyses; Sequence Analysis; Shotgun Sequencing; Staging; Surface; Survey Instrument; Surveys; Technology; Testing; Time; trait; Transmission; transmission process; Typing, Blood; Variation (Genetics); Vivax Malaria; youngster
Relevance: - Today 2.6 billion people live in areas of risk for Plasmodium vivax (Pv) transmission; 106 - 313 million cases of vivax malaria annually. Duffy blood group negativity has been considered to confer resistance to vivax malaria, however, our recent findings indicate that Pv has gained the capacity to infect erythrocytes and cause disease in Duffy-negative people in Madagascar, suggests that Pv has acquire new erythrocyte infection mechanisms. Through whole genome sequence analysis we will reveal differences between Pv strains infecting Duffy-negative vs. Duffy-positive people that will help identify genes evolving to expand the erythrocyte invasion capacity of Pv
Project start date: 2011-02-15
Project end date: 2013-01-31
Budget start date: 15-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-10-069
1R21AI093922-01 (2011): $274750
INTERNATIONAL CONFERENCE FOR THE SOCIETY FOR INTEGRATIVE ONCOLOGY
A Peter
Indiana Univ-purdue Univ At Indianapoliscity: Indianapolis country: United States (us)
Grant 1R13CA144223-01A1 from National Cancer Institute
Abstract: Through its annual conferences, the Society for Integrative Oncology (SIO) provides a significant forum for presentation of current research and ground-breaking clinical applications of Complementary and Alternative Medicine (CAM) therapies in cancer care. Moreover, these conferences provide an atmosphere conducive to the exchange of important information, while promoting a deeper appreciation of how CAM can combine with conventional approaches in medicine to achieve optimal therapeutic outcomes for cancer patients. These objectives work in accordance with the mission of the NIH, as a mechanism of "science in pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce the burdens of illness and disability." These critical, high-level scientific conferences have been held annually since 2005, providing meaningful, current data on the integration of CAM modalities in the conventional care of cancer patients. This year, the venue is again New York -home to an expansive, forward thinking medical population that includes researchers and clinicians from some of the most prestigious traditional and complementary medicine training and research programs in the country. The large number of local CAM professionals is thus leveraged not only as a potential audience, but as members of the Faculty. The non-profit Society for Integrative Oncology (SIO) was established to be the prime driving force for the reasoned application of evidence-based CAM therapies into conventional cancer care. The SIO is the main sponsor of this conference; the Scientific Program Committee includes senior professionals from major cancer centers throughout the United States and member countries. We anticipate over 300 attendees, primarily active CAM and conventional practitioners involved in cancer patient care. A large minority of oncologists is expected to take part. The specific aims of this application are to establish an annual evidence-based meeting to 1) introduce recent clinical and basic science evidence regarding Integrative therapies in cancer care to new and established investigators; 2) promote collaboration between national and international centers of excellence in Integrative Oncology to enhance availability of high quality research in complementary and alternative methods of symptom management; 3) provide continuing education and a forum for exchange of future research ideas between experienced investigators and integrative practitioners. Complementary and Alternative medical (CAM) therapies are used by a large majority of cancer patients, usually without sufficient research into their mechanisms of action, efficacy, or toxicity. The Society for Integrative Oncology (SIO) is devoted to the prudent research and clinical application of CAM therapies in cancer. The annual SIO International Conference, and the Society´s journal, serve as vehicles to review and discuss research and clinical outcomes of CAM use in the oncology milieu
Keywords: Basic Science; Behavior; burden of illness; cancer care; Cancer Center; Cancer Patient; Caring; Clinical; clinical application; Clinical Sciences; Collaborations; Complementary and alternative medicine; Complementary Medicine; Continuing Education; Country; Data; disability; driving force; evidence base; experience; Faculty; Home environment; International; international center; Journals; Knowledge; Life; Malignant Neoplasms; Medical; Medicine; meetings; member; Methods; Minority; Mission; Modality; Nature; New York; Oncologist; oncology; Organism; Outcome; Patient Care; planetary Atmosphere; Population; programs; Research; Research Personnel; Research Training; Science; Societies; symposium; symptom management; Therapeutic; Thinking, function; Toxic effect; Traditional Medicine; United States; United States National Institutes of Health; Work
Relevance: Complementary and Alternative medical (CAM) therapies are used by a large majority of cancer patients, usually without sufficient research into their mechanisms of action, efficacy, or toxicity. The Society for Integrative Oncology (SIO) is devoted to the prudent research and clinical application of CAM therapies in cancer. The annual SIO International Conference, and the Society´s journal, serve as vehicles to review and discuss research and clinical outcomes of CAM use in the oncology milieu
Project start date: 2011-09-01
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-10-071
1R13CA144223-01A1 (2011): $12000
REDUCING HEALTH SYSTEMS COSTS THROUGH A PATIENT-ACTIVATION RCT
A Peter, Assistant Professor Of Health Policy And
Columbia University Health Sciencescity: New York country: United States (us)
Grant 1R21HD071561-01 from Office Of The Director, National Institutes Of Health
Abstract: This R21 proposal is submitted in response to RFA-RM-10-015 the Economics of Prevention. Our proposed randomized controlled trial (RCT) is designed to determine whether well-informed patients can persuade doctors to reduce the number of inappropriate screening tests and increase the number of appropriate preventive screening tests that are ordered during routine medical visits. Up to 93% of doctors self-report ordering unnecessary tests. Unnecessary tests are those that, on balance, appear to produce more harm than good. Harm to the patient can arise directly from the test (e.g., infection, bleeding, or exposure to radiation) or from false positive test results. False positive test results often produce psychological distress for the patient by leading to further invasive testing. Inappropriate testing can also cause indirect harm by needlessly increasing health system costs, and has been estimated to cost between $50 billion and $650 billion annually. Medical care costs outstrip consumer inflation, and cost increases threaten the long-term viability of the Patient Protection and Affordable Care Act (PPACA). A wide range of studies has shown that well-informed patients can influence physician behavior. We have the unique opportunity to randomly assign approximately 1,128 predominately young and healthy female employees at a large Silicon Valley technology firm to either receive a 3patient activation intervention plus a health message or to receive the message alone. The patient activation intervention entails the use of an innovative education tool to inform patients regarding the appropriate clinical practice for their age, gender, and general risk factors for disease. It also provides guidance on how to communicate appropriate test ordering behavior with their physician. Follow-up will be monitored automatically via billing systems and web-based self-administered surveys, allowing us to conduct an RCT at very low cost. We will then use these data to conduct a cost- effectiveness analysis of the intervention. We will also, for the first time, use RCT data to explore psychological distress induced by false positive mammograms among women under 50 years of age who have no risk factors for breast cancer. Patient activation is a politically neutral and innovative means of increasing the efficiency of preventive healthcare delivery in the U.S. It has the potential to optimize preventive service delivery within PPACA. But its effectiveness will be greatest if it changes the culture of medicine by spreading within patient and provider social networks. Therefore, in addition, this study will also serve to pilot an R01 to track behavior change as an intervention spreads through the 12,500 employees within the social network of a large Silicon Valley technology firm and their provider networks. Information gathered from these programs-in the form of subject interaction tracking via Global Positioning Service-will eventually inform an agent-based systems model examining strategies for improving the efficiency of the US health care system. We propose a randomized controlled trial of a novel intervention to reduce inappropriate preventive testing (and increase appropriate testing) through a patient activation intervention. This grant forwards a path to improving preventive care and reducing health system costs under the Patient Protection and Affordable Care Act that is less politically contentious than previous proposals, as agency is placed on the patient rather than removed from the provider
Keywords: Age; Age-Years; American; base; Behavior; behavior change; billing data; Biological Models; Breast Cancer Risk Factor; Caring; Cellular Phone; Chemistry; clinical practice; cohort; Collection; comparative effectiveness; Complete Blood Count; Computer software; cost; cost effectiveness; Cost Effectiveness Analysis; Data; design; Developed Countries; Disease; disorder risk; Economic Inflation; Economics; Educational aspects; Effectiveness; Employee; Equilibrium; Exposure to; Female; follow-up; Funding; Future; Gender; Grant; Health; health care delivery; Health Expenditures; Health Insurance; health related quality of life; Health system; Healthcare Systems; Hemorrhage; Human; improved; indexing; Infection; Information Dissemination; information gathering; Information Services; innovation; Insurance; Interpersonal Relations; Intervention; Low income; Mammography; markov model; Measures; Medical; Medical Care Costs; Medical Electronics; Medicine; Monitor; Nature; novel; Online Systems; Outcome; Patient Self-Report; Patients; Personal Satisfaction; Persons; Physicians; Population; Positioning Attribute; Positive Test Result; post intervention; Prevention; Preventive; Preventive Intervention; Preventive screening; Procedures; programs; Provider; psychologic; psychological distress; Quality-Adjusted Life Years; Radiation; Randomized; Randomized Controlled Trials; Recruitment Activity; Research; research study; Resources; response; Risk; Risk Factors; Screening procedure; Self-Administered; Series; Services; Silicon; Simulate; simulation; Social Network; software systems; Surveys; Symptoms; System; Technology; Testing; time use; tool; Variant; Visit; Woman
Relevance: We propose a randomized controlled trial of a novel intervention to reduce inappropriate preventive testing (and increase appropriate testing) through a patient activation intervention. This grant forwards a path to improving preventive care and reducing health system costs under the Patient Protection and Affordable Care Act that is less politically contentious than previous proposals, as agency is placed on the patient rather than removed from the provider
Project start date: 2011-09-16
Project end date: 2013-08-31
Budget start date: 16-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-RM-10-015
1R21HD071561-01 (2011): $240000
MICROBICIDE DEVELOPMENT PROGRAM (MDP)
A Peter, Co-director, Ucla Ibd Center
University Of California Los Angelescity: Los Angeles country: United States (us)
Grant 3U19AI060614-05S1 from National Institute Of Allergy And Infectious Diseases
Abstract: This proposal addresses the need to develop a rational, cost effective, and scientifically robust approach to the development of topical rectal microbicides from preclinical to exploratory studies in humans. The individual projects explore distinct, but overlapping areas of microbicide research that, cumulatively, will define the future of rectal microbicide development. The key premise that underpins the proposal is that receptive anal intercourse (RAI) is a common activity, playing a significant role in the transmission of HIV infection. Heterosexual RAI is common, with rates of 5-10% in US women and is considered to be the most common route of HIV transmission in men who have sex with men. Failure to acknowledge the role that RAI plays in the global AIDS pandemic is likely to limit the success of intervention strategies and compromise attempts to develop safe and effective vaginal microbicides. This MDP Project application is a U19, a collaborative effort with NIH and private sectors, to initiate coordinated, multidisciplinary research involving many of the world´s experts in disciplines related to rectal microbicide development. We have focused our efforts on one class of microbicides, the reverse-transcriptase (RT) inhibitors (PMPA, UC-781, and TMC-120), two of which are in clinical trials as vaginal microbicide form. We have the support of three corporate sponsors (Biosyn, Inc., Gilead Sciences, and Tibotec-Virco) to initiate these efforts. The "preclinical" phase includes cell line, intestinal explant and macaque studies of microbicide safety and efficacy (Project by McGowan) which will progress microbicides into exploratory human trials designed to optimize microbicide safety evaluation, provide initial ex vivo/in vitro efficacy data, and information about distribution and bioavailability of RT microbicides (Project by Corner). The goal, over 5 years, will be to assess, what are the most cost effective and predictive assays for use in future microbicide development. Projects by Gorbach will target the role of RAI on mucosal function, the behavioral correlates of RAI, and acceptability studies of candidate formulations. Failure to adjust for these modifiers of safety and efficacy may result in (1) falsely attributing RAI toxicity to the microbicide and (2) failing to demonstrate efficacy because of simultaneous enhancement of HIV transmission due to RAI. The information derived from these studies will be critical for RT development, but will also provide a rational basis for the development of other classes of rectal microbicides
Project start date: 2004-08-15
Project end date: 2011-07-31
Budget start date: 18-SEP-2009
Budget end date: 31-JUL-2011
PFA/PA: PAR-03-137
3U19AI060614-05S1 (2009): $2071249
3U19AI060614-05S2 (2009): $121998
5U19AI060614-05 (2008): $4184742
Sponsored Links Excellgen http://Excellgen.com
EFFECTIVENESS TRIAL OF YOUTH SUICIDE PREVENTION DELIVERED BY TEEN PEER LEADERS
A Peter, Associate Professor
University Of Rochestercity: Rochester country: United States (us)
Grant 5R01MH091452-02 from National Institute Of Mental Health
Abstract: This project responds to the need for (1) scientifically rigorous evaluations of interventions to prevent suicide in adolescents, and for (2) school-based suicide prevention programs that are suitable for rural and underserved communities where there is a scarcity of mental health services. Suicide accounts for more deaths among 10 - 24 year olds in the US than all natural causes combined; each year 5 - 9% of adolescents attempt suicide and 700,000 require medical attention. In most rural regions, adolescent suicide rates are 2 - 10 times above the US national average. This proposal seeks RO1 funding for a randomized controlled trial to evaluate the effectiveness of the Sources of Strength (SoS) intervention in reducing rates of attempted suicide among adolescents in rural communities. SoS builds social-ecological protective influences across a full population of high school students to reduce the likelihood that vulnerable youth will become suicidal and connects suicidal youth to capable adults at school and in the community. Trained ´peer opinion leaders´ change the norms of students throughout their schools regarding the acceptability of suicide, help-seeking and youth-adult communication by conducting a set of well-defined messaging activities with ongoing adult mentoring. This approach draws on the major influence of adolescent peers that is powerful enough to affect drug use, sexual practices and other health behaviors. We have completed work to prepare SoS for a large scale trial, including conducting a preliminary study using a randomized design in 18 schools showing that the intervention modifies the norms of students school-wide about suicide and help seeking, with the largest changes occurring among suicidal youth. For the proposed 5-year study, 36 rural high schools in New York and North Dakota will be randomly assigned to immediate SoS or wait-list control conditions. We will survey students in the schools over 18 months to (1) compare intervention and control levels of self-reported suicide attempts, (2) determine differences in impact for low- and high-risk groups, (3) test multiple hypothesized mediators of SoS impact on reducing suicide attempts from our intervention causative model, (4) use social network methods in a subset of schools to identify network mediators of SoS impact, the extent of dissemination of peer-to-peer messages, and evaluate the efficiency of the current strategy for identifying student peer leaders. This project can have a positive public health impact through the potential to prepare a cost-effective intervention that can be implemented safely in diverse communities and is effective in reducing suicidal behaviors among adolescents. This proposed 5-year project can have a positive public health impact by preparing Sources of Strength (SoS), a school-based suicide prevention intervention, for expansion as a cost-effective program that can be implemented safely in diverse communities and is effective in reducing suicidal behaviors among adolescents. The proposed study can also contribute to knowledge needed to strengthen social-ecological protective influences across a full population of high school students by peer opinion leaders to change the norms of students through their schools and reduce suicidal behaviors
Keywords: Accounting; Address; Adolescent; Adult; Affect; Age; age group; Attitude; base; Behavioral; Cause of Death; Cessation of life; Clinical Trials Design; Communication; Communities; coping; cost effective; Coupled; Data; density; design; Diffusion; Distress; Drug usage; Educational Curriculum; effective intervention; Effectiveness; effectiveness trial; Ethnicity aspects; Evaluation; Exercise; Female; Funding; Gatekeeping; Health behavior; Health Knowledge, Attitudes, Practice; Health system; help-seeking behavior; high risk; high school; Hylobates Genus; Influentials; Internet; Intervention; intervention effect; Knowledge; Link; male; Measures; Mediating; Mediator of activation protein; medical attention; Mental Health; Mental Health Services; Mentors; Methodology; Methods; Modeling; Moods; National Center for Health Statistics (U.S.); New York; North Dakota; novel; Pathway Analysis; Patient Self-Report; peer; Peer Group; peer influence; Perception; Performance; Population; Prevention program; Preventive Intervention; Problem behavior; programs; Proliferating; Protocols documentation; public health medicine (field); public health relevance; Race; Randomized; Randomized Controlled Trials; Recording of previous events; Recruitment Activity; reducing suicide; Reliance; Research Infrastructure; research study; response; Risk; Risk Factors; Rural; Rural Community; Sampling; Schools; Screening procedure; Secure; Services; Site; social; social integration; Social Network; social networking website; Source; strength training; Students; Subgroup; substance abuse prevention; Substance abuse problem; suicidal; suicidal adolescent; suicidal behavior; Suicide; Suicide attempt; Suicide prevention; suicide rate; Surveys; Teenagers; Testing; Time; Training; Victimization; Violence; Waiting Lists; Work; young adult; Youth
Project start date: 2010-07-28
Project end date: 2015-02-28
Budget start date: 1-MAY-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-07-070
5R01MH091452-02 (2011): $534254
TRAINING GRANT IN VIRAL AND CHEMICAL CARCINOGENESIS
A Peter, Professor
University Of Southern Californiacity: Los Angeles country: United States (us)
Grant 5T32CA009320-27 from National Cancer Institute
Abstract: This is a renewal application for a postdoctoral training program in cancer biology based at the USC/Norris Comprehensive Cancer Center at the USC Keck School of Medicine. The principal goal of this program is to continue to provide Ph.D. and M.D. postdoctoral trainees with an interdisciplinary research experience of the highest quality. The program has four key elements. First and most importantly, trainees will conduct research under the supervision of a member of the Morris faculty; second, trainees will attend Grand Rounds, a seminar series that brings together clinicians and basic scientists on topics of mutual interest; third, trainees will present their work at one or more discipline-based research seminars, including eukaryotic gene regulation, epigenetics, and developmental biology; finally, trainees will have the option of attending didactic courses in a variety of subjects related to cancer biology, including courses in molecular genetics, human genetics, developmental biology, pathology, cancer biology, responsible conduct in research (required), and computational biology. These intensive graduate-level courses, which serve as a foundation of the highly successful, multi-departmental Program in Biological and Biomedical Sciences (PIBBS), will enable trainees to enhance their background in areas of cancer biology and medicine. The proposed program, in short, will provide trainees with both the practical experience and the scientific knowledge necessary for them to function as members of an interdisciplinary team whose goal is to translate basic discoveries into clinically useful approaches
Keywords: chemical carcinogenesis; Grant; Training; viral carcinogenesis
Project start date: 1979-08-01
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5T32CA009320-27 (2011): $284136
REGULATION OF LUNG INFLAMMATION BY CATECHOLAMINES AND ADRENERGIC RECEPTORS
A Peter
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5R01GM029507-29 from National Institute Of General Medical Sciences
Abstract: These studies will evaluate the role of the adrenergic system in regulation of the acute inflammatory response, especially in the setting of acute lung injury (ALI). In Aim 1, we will evaluate lung dendritic cells (DCs), lung macrophages and alveolar epithelial cells (AECs) for the presence of a2 adrenergic receptors (a2A, a2B, a2C) as well as inducible catecholamine synthases and hydrolases, and how these receptors and enzymes affect cell responses to C5a, LPS, or both. In Aim 2, we will evaluate adrenergic regulation of the local inflammatory response (ALI following pulmonary deposition of LPS or IgG immune complexes) and the systemic inflammatory response ("cytokine storm" following cecal ligation and puncture, CLP). In Aim 3, we will evaluate the three cell types (described above) for their ability to respond to C5a or LPS, or both, resulting in enhanced cytokine responses via epigenetic changes occurring in these cells. In Aim 4, we will assess the role of ¿2AR agonists in ALI, pursuing preliminary evidence that ALI, following intrapulmonary deposition of LPS or IgGICs, is greatly attenuated by the presence of specific isomeric forms of albuterol and formoterol. We will assess the molecular mechanisms for the protective effects of 22AR agonists, including effects on signaling pathways. Collectively, these studies should demonstrate how the adrenergic system regulates the acute inflammatory response, especially in the lung. Acute lung inflammation involving the upper airways (as in asthma, COPD, cystic fibrosis) or the lower airways (as in acute lung injury [ALI] or acute respiratory distress syndrome [ARDS]) affects millions of individuals in North America, resulting in high morbidity and mortality. The mechanisms of these lung inflammatory disorders are poorly understood. The proposed work will relate to our recent discoveries that the adrenergic nervous system plays an important role in acute lung inflammation and can be manipulated for therapeutic benefit
Keywords: Acids; Acute; adrenergic; Adrenergic Agents; Adrenergic Receptor; Adult Respiratory Distress Syndrome; Affect; Agonist; Airway Resistance; Albuterol; Alveolar; Alveolar Macrophages; Anti-inflammatory; Anti-Inflammatory Agents; Antigen-Antibody Complex; Asthma; Attenuated; autocrine; base; Bone Marrow; Breathing; Burn injury; catecholamine inhibitor; Catecholamines; cell type; Cells; Chronic Obstructive Airway Disease; Complement 5a; Cyclic AMP; Cystic Fibrosis; cytokine; Data; Dendritic Cells; Deposition; design; Disease; Environmental air flow; Enzymes; Epigenetic Process; Epithelial Cells; Event; Experimental Models; Exposure to; Feedback; formoterol; Human; Hydrolase; Immunoglobulin G; improved; In Vitro; Incubated; Individual; Inflammation Mediators; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; inhibitor/antagonist; Interleukin-6; Intervention; Ligation; Liquid substance; Local Acute Inflammatory Response Pathway; Lung; Lung Inflammation; lung injury; Lung Injury, Acute; macrophage; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Mortality Vital Statistics; Mus; Muscle relaxation phase; Nervous system structure; Non-Steroidal Anti-Inflammatory Agents; North America; Patients; Phagocytes; Pharmaceutical Preparations; Pharmacologic Substance; Play; Production; Prone Position; protective effect; public health relevance; Publications; Puncture procedure; Rattus; receptor; Regulation; Relative (related person); Relaxation; Reperfusion Injury; research study; Respiratory physiology; response; Role; Sepsis; Sheep; Signal Pathway; Skin; smoke inhalation; Smooth muscle (tissue); Smooth Muscle Myocytes; Sodium Chloride; Structure; surfactant; System; Therapeutic; TNF gene; Water; Work
Relevance: Acute lung inflammation involving the upper airways (as in asthma, COPD, cystic fibrosis) or the lower airways (as in acute lung injury [ALI] or acute respiratory distress syndrome [ARDS]) affects millions of individuals in North America, resulting in high morbidity and mortality. The mechanisms of these lung inflammatory disorders are poorly understood. The proposed work will relate to our recent discoveries that the adrenergic nervous system plays an important role in acute lung inflammation and can be manipulated for therapeutic benefit
Project start date: 1982-07-01
Project end date: 2014-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-07-070
5R01GM029507-29 (2011): $309438
CONFERENCE ON CLINICAL RESEARCH FOR RARE DISEASES
A Peter, Associate Professor
Boston University Medical Campuscity: Boston country: United States (us)
Grant 5R13NS067968-02 from National Institute Of Neurological Disorders And Stroke
Abstract: There are more than 6,000 diseases classified as "rare" (defined as having a prevalence in the United States of <200,000 persons). While individually these entities are uncommon, as a group they are an important cause of chronic illness, disability and premature death in both children and adults. Despite their rarity, many fundamental advances in medicine have come from the study of rare diseases and these have benefited common diseases. Both because of currently inadequate therapy and the potential to assist common as well as rare disorders, the conduct of clinical research in rare diseases is essential. In order to assure the future of this research, the training of the next generation of investigators in this field is important. The NIH Rare Diseases Clinical Research Network (RDCRN, www.RareDiseasesNetwork.org) and the NIH Clinical and Translational Science Award Program are the ideal groups to sponsor a conference addressing rare diseases research methodology that would supplement general training in clinical research and attract trainees and junior faculty into this important field. In 2007 the RDCRN held the inaugural "Conference on Clinical Research for Rare Diseases". This Conference, supported by an R13 grant was a tremendous success, attracted 200 attendees, fulfilled all the goals of the Organizing Committee and NIH sponsors, and received outstanding scores on evaluations. This R13 grant proposes to support the "Conference on Clinical Research for Rare Diseases" in 2010 and 2012. These Conferences will provide information and resources to trainees and junior faculty that they can directly apply to their work and career development. The proposed conference format is of a full day program made up of short didactic lectures and panel discussions on focused areas relevant to the attendee´s current stage of career and research development. The issues that will be addressed include 1) creating research networks, 2) study design and biostatistics in dealing with a small number of subjects, 3) utilizing the CTSA program for rare diseases research, 4) pathways for developing orphan products, 5) working with industry, 6) conflict of interest in rare diseases research, 7) the roles of patient advocacy groups in rare diseases research; and 8) career advice. There will also be poster presentations, so that trainees can share with each other and with senior investigators of the RDCRN their current research and receive feedback. The final session will be a dinner with a keynote address given by a prominent clinical scientist. Members of the RDCRN Steering Committee (Consortia PIs, NIH program officials from multiple institutes, and patient advocacy group representatives) as well as investigators within the CTSA Program will participate in the conference. There will be an evaluation component where participants will fill out a form indicating the level of success in achieving our goals. Finally, the proceedings will be posted on the web and a summary article will be published. The proposed conference will provide trainees and junior faculty engaged in clinical investigation in rare diseases with practical education in research methodologies specifically focused on studying rare disorders. By encouraging and assisting young clinical investigators involved in rare disease research, this conference will not only promote discovery of new insights into pathophysiology and treatment of rare diseases, but also result in all of the collateral benefits to general medical science and public health that rare disease research has provided throughout history
Keywords: Address; Adult; Area; Award; Biometry; career; career development; Cessation of life; Child; Chronic Disease; Clinical; Clinical Investigator; Clinical Research; Clinical Sciences; Clinical Trials; Conflict of Interest; disability; Disease; Educational aspects; Evaluation; Faculty; Feedback; Functional disorder; Future; Goals; Grant; Industry; insight; Institutes; Internet; lectures; Medical; Medicine; member; next generation; Orphan; Participant; Pathway interactions; patient advocacy group; Persons; posters; premature; Prevalence; programs; public health medicine (field); public health relevance; Publishing; Rare Diseases; Recording of previous events; Research; research and development; Research Design; Research Methodology; Research Personnel; Research Training; Resources; Role; Science; Scientist; Staging; success; symposium; Training; Translational Research; United States; United States National Institutes of Health; Work
Relevance: The proposed conference will provide trainees and junior faculty engaged in clinical investigation in rare diseases with practical education in research methodologies specifically focused on studying rare disorders. By encouraging and assisting young clinical investigators involved in rare disease research, this conference will not only promote discovery of new insights into pathophysiology and treatment of rare diseases, but also result in all of the collateral benefits to general medical science and public health that rare disease research has provided throughout history
Project start date: 2010-04-01
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-08-149
5R13NS067968-02 (2011): $1
PRE-DOCTORAL RESEARCH TRAINING IN AGING AND URBAN HEALTH
A Peter, Director/professor
Wayne State Universitycity: Detroit country: United States (us)
Grant 3T32AG000275-10S1 from National Institute On Aging
Abstract: The Wayne State University training program in aging and urban health is seeking funds to continue its exceptional pre-doctoral research training program. The rationale for continuing this NIH supported training program is to further our success in training pre-doctoral students, across.avariety of disciplines, on the study of aging and urban health, with a focus on health disparities, functional independence, cognitive neuroscience as well as health and health care over another 5 year period. Our model of using mentoring teams and "pseudo joint appointments" has enabled our trainees to develop a strong professional "fit" with gerontology. This is illustrated by the fact that all 17 of our graduates from 2001-present hold positions in aging and health research at top universities or research programs (e.g. Duke University, University of Michigan, University of California-Davis, University of Louisville, North Carolina State University, City University of London, University of Manchester, University of Miami, Research Triangle Institute). The NIA´s investments have led to exceptional success by trainees 72 publications, 103 regional and national presentations, over 50 university and national awards. From 2001-2004-05, for each slot, the NIA awarded (20 over first four years), we have been able to award an additional 53 slots through university commitments and training faculty research grants. Indeed,one of the keys to an exceptional training setting is the presence of hihgly skilled funded researchers. Our 21 training faculty hold over $30,000,000 in grant funding, a doubling from our first application five years ago. Program Excellence is demonstrated by (1) Trainee achievement, (2) Faculty achievement, (3) Program achievement, and by (4) Demonstrating growth in its reputation and widespread impact across campus, in the community, and nationally. Lay Behavioral, social and cognitive neuroscience research holds significant promise for better understanding chronic disease, health promotion and health-related behaviors among older adults. This is particularly true for urban older adults, who suffer significantly increased morbidity and mortality due to health disparities across a spectrum of diseases and conditions such as diabetes, hypertension, obesity, and a variety of physical and cognitive disabilities. Our training program will prepare researchers to be able to design and apply research findings to this population
Keywords: Aging; pre-doctoral; Research Training; Urban Health
Project start date: 2000-04-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
3T32AG000275-10S1 (2011): $140501
VASCULITIS CLINICAL RESEARCH CONSORTIUM
A Peter, Associate Professor
Boston University Medical Campuscity: Boston country: United States (us)
Grant 5U54AR057319-08 from Office Of The Director, National Institutes Of Health
Abstract: The Vasculitis Clinical Research Consortium (VCRC) was established in 2003 and in 5 years of rapid growth and productivity has become the major clinical research infrastructure in North America dedicated to the study of vasculitis. The VCRC is a founding member and leading force of the NIH Rare Diseases Clinical Research Network (RDCRN). By conducting a series of longitudinal cohort studies, biomarker discovery projects, multicenter clinical trials, and outcome measure development projects, the Consortium is addressing serious unmet medical and scientific needs for this group of complex rare diseases. The VCRC currently has over 500 patients in clinical research on the following 6 types of vasculitis giant cell arteritis, Takayasu´s arteritis, polyarteritis nodosa, Wegener´s granulomatosis, microscopic polyangiitis, and Churg Straus Syndrome. Each of these diseases are consider "orphan" diseases. Additionally, partnership with patient advocacy groups has been a critical component to the success of the VCRC. The VCRC electronic resources are important for patients worldwide. The VCRC Fellowship Program has successfully trained new clinical investigators, each of whom remains engaged in academic research in vasculitis. This proposal outlines a total of 13 separate clinical protocols with 10 associated studies of biomarkers VCRC investigators have successfully obtained ancillary funding to allow for expansion of the Consortium´s work. Sources of these funds include the NIH, the FDA, private foundation and the biopharmaceutical industry. This application seeks refunding of the VCRC to both support the critical administrative, laboratory, biostatistical cores and allow completion of ongoing projects, launch of exciting new scientific initiatives training of new investigators in clinical research in vasculitis, and expansio n of the VCRC website
Keywords: Academic Medical Centers; Address; Biological Products; biomarker; Churg-Strauss Syndrome; Clinical; Clinical Investigator; Clinical Protocols; Clinical Research; Clinical Trials; Cohort Studies; Complex; Data; Development; Disease; double-blind placebo controlled trial; Educational process of instructing; Electronics; Fellowship Program; Foundations; Funding; Funding Agency; Industry; Laboratories; Longitudinal Studies; Medical; member; Methodology; Microscopic polyangiitis; North America; novel therapeutics; Orphan Disease; Outcome Measure; patient advocacy group; Patients; Phase; Physicians; Pilot Projects; Polyarteritis Nodosa; Productivity; programs; Randomized; rapid growth; Rare Diseases; Registries; repository; Research; Research Infrastructure; Research Personnel; Research Project Grants; Resources; Series; Specimen; success; Takayasu`s Arteritis; Temporal Arteritis; Training; Translational Research; United States National Institutes of Health; Vasculitis; web site; Wegener`s Granulomatosis; Work
Relevance: The Vasculitis Clinical Research Consortium (VCRC) combines the clinical and scientific expertise of several major academic medical centers in North America to conduct a series of research projects in several types of vasculitis. Vasculitis is a serious but rare set of diseases and the combined efforts of the VCRC investigators will seek to address important unanswered questions about the causes and best treatments for vasculitis. The VCRC will also teach other physicians about vasculitis and will work closely with vasculitis patient advocacy groups
Project start date: 2003-09-30
Project end date: 2014-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-OD-08-001
5U54AR057319-08 (2011): $1227000
USC NORRIS COMPREHENSIVE CANCER CENTER (CORE) SUPPORT
A Peter, Professor
University Of Southern Californiacity: Los Angeles country: United States (us)
Grant 2P30CA014089-36 from National Cancer Institute
Abstract: The USC Norris Comprehensive Cancer Center at the University of Southern California was founded in 1971 and has been continuously supported by a Cancer Center Support Grant since 1973. It has developed into a major regional and national resource for cancer research, treatment, prevention and education. Center facilities have been built and developed with support from the NCI, the University and the Kenneth Norris Jr. Cancer Hospital, which is an integral part of the Cancer Center. The Center underwent a major expansion with the addition of the Norman Topping Tower in 1996 and the Harlyne Norris Research Tower in 2007. The Center´s 198 members are organized into five thematic and five translational research programs, including a "bridge" program in developmental therapeutics. The thematic programs are headed by senior investigators in the fields of molecular genetics, epigenetics and regulation, tumor microenvironment, cancer epidemiology and cancer control research. The translational programs, which provide focus to our transdisciplinary research efforts, are in developmental therapeutics, genitourinary cancers, gastrointestinal cancers, women´s cancers and leukemia and lymphoma. This application is for 1) partial salary support for the Center´s senior leadership, who are responsible for planning and overseeing our research efforts; 2) support for program planning and evaluation to keep the Center at the forefront of cancer research; 3) support for the administrative infrastructure of the Center; 4) partial support for the Center´s 11 shared resources which facilitate the conduct of our peer-reviewed research; and 5) support for developmental funds to help us recruit new investigators in areas we have targeted for expansion and to fund innovative pilot projects. Continued funding from the Cancer Center Core Support Grant will allow us to build on our strengths in basic and population-based research and to translate our underlying expertise into strong, peer-reviewed funded research programs focused on cancers of major consequence in this country. Cancer Center members currently hold grants totaling $125 million in direct costs, with $43 million of that coming from NCI (all exclusive of the CCSG). RELEVANCE The USC Norris Comprehensive Cancer Center provides the infrastructure and resources to facilitate and foster translational research for the development of more effective prevention, diagnosis, treatment of cancer
Project start date: 1996-12-01
Project end date: 2015-11-30
Budget start date: 9-JUN-2011
Budget end date: 30-NOV-2011
2P30CA014089-36 (2011): $3232044
3P30CA014089-36S1 (2011): $50000
3P30CA014089-36S2 (2011): $244500
3P30CA014089-36S3 (2011): $74923
Sponsored Links Excellgen http://Excellgen.com
THE BIOORGANIC CHEMISTRY OF RNA EDITING BY ADARS
A Peter, Professor
University Of California Daviscity: Davis country: United States (us)
Grant 2R01GM061115-10A1 from National Institute Of General Medical Sciences
Abstract: The RNA editing ADAR enzymes convert adenosines to inosines in RNA. Since inosine is decoded as guanosine during translation, this modification can lead to changes in the meaning of codons (recoding). There are at least 50 different A to I sites in human mRNAs that cause recoding. Recoding is common in the nervous system with targets including ligand-gated ion channels, voltage-gated ion channels and G-protein coupled receptors. Indeed, ADARs are necessary for a properly functioning nervous system and are known to regulate behavior in metazoans. However, little is known about the effect of recoding for targets with roles outside the nervous system. Perturbations in A to I editing have been observed in several human diseases including amyotrophic lateral sclerosis (ALS), dyschromatosis symmetrica hereditaria (DSH), Prader-Willi syndrome (PWS), epilepsy, depression and cancer. A recent study also implicates ADARs in the control of aging. Despite the significance of this form of epigenetics, our understanding of the mechanism and regulation of A to I editing is deficient. For instance, the selectivity for specific adenosines within ADAR substrates remains difficult to fully explain due to a lack of detailed characterization for ADAR-RNA complexes. Furthermore, pharmacological methods for controlling RNA editing do not currently exist limiting the types of studies possible to probe its biological function. In this competitive renewal of an R01 project, these knowledge gaps will be addressed through the application of synthetic chemistry coupled with techniques from molecular biology and biochemistry. The results of these studies will extend our basic understanding of the process of RNA editing and its effects on protein function as well as lead to new methods for its control. Methods for site-selective inhibition of RNA editing will be developed. Backbone modified antisense oligonucleotides and helix- threading peptoids that target RNA editing substrates will be investigated for this purpose. In addition, we will define factors controlling editing selectivity and mechanisms of inhibition for the ADAR2 reaction. A functional screen will be used to define the importance in controlling editing site selectivity of the length and sequence in a linker structure between two ADAR2-RNA interaction domains. In addition, ADAR2 mutants containing unnatural amino acids and RNA containing nucleoside analogs will be used to map ADAR2-RNA interactions. A novel genetic selection will identify cyclic peptide inhibitors of ADAR2 and follow-up studies with these inhibitors will identify points in the ADAR2 reaction susceptible to small molecule control. In addition, we will define the basis for ADAR1 editing of the mRNA for the DNA repair enzyme NEIL1. These efforts will define structure/activity relationships for the ADAR1 reaction and extend our understanding of the recoding of targets with functions outside the nervous system. Finally, this project will produce new molecules for crystallization trials of ADAR-RNA complexes. RNA editing catalyzed by the ADAR enzymes is a form of epigenetic control of gene expression that is perturbed in a variety of human diseases including amyotrophic lateral sclerosis (ALS), dyschromatosis symmetrica hereditaria (DSH), Prader-Willi syndrome (PWS), epilepsy, depression and cancer. The proposed studies will extend our basic understanding of the process of RNA editing as well as lead to new methods for its control
Keywords: ADAR1; Address; Adenosine; Aging; Amino Acids; Amyotrophic Lateral Sclerosis; Antisense Oligonucleotides; base; Behavior; Biochemistry; Biological Process; Chemistry; Codon Nucleotides; Complex; Coupled; Crystallization; Cyclic Peptides; Deaminase; Deamination; DNA Repair; DNA Repair Enzymes; DRADA2b protein; Enzymes; Epigenetic Process; Epilepsy; follow-up; G-Protein-Coupled Receptors; Gated Ion Channel; Gene Expression; Genetic Techniques; Guanosine; Human; human disease; inhibitor/antagonist; Inosine; Knowledge; Lead; Length; Ligands; Link; Malignant Neoplasms; Maps; Mental Depression; Messenger RNA; Methods; Modification; Molecular Biology Techniques; mRNA Precursor; mutant; Nervous System Physiology; Nervous system structure; novel; nucleoside analog; Peptoids; Prader-Willi Syndrome; Process; protein function; Proteins; public health relevance; Reaction; Regulation; Reporting; Research; Research Design; RNA; RNA Binding; RNA Editing; Role; Saccharomyces cerevisiae; Selection (Genetics); Site; small molecule; Structure; Structure-Activity Relationship; Synthesis Chemistry; Testing; Therapeutic; Time; Tissues; tool; Transcript; Translations; Vertebral column; voltage
Relevance: RNA editing catalyzed by the ADAR enzymes is a form of epigenetic control of gene expression that is perturbed in a variety of human diseases including amyotrophic lateral sclerosis (ALS), dyschromatosis symmetrica hereditaria (DSH), Prader-Willi syndrome (PWS), epilepsy, depression and cancer. The proposed studies will extend our basic understanding of the process of RNA editing as well as lead to new methods for its control
Project start date: 2000-04-01
Project end date: 2015-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-10-067
2R01GM061115-10A1 (2011): $278746
5R01GM061115-09 (2009): $237912
SUNITINIB MODULATION OF CANCER IMMUNOTHERAPY
A Peter, Staff
Cleveland Clinic Lerner Col/med-cwrucity: Cleveland country: United States (us)
Grant 5R01CA150959-02 from National Cancer Institute
Abstract: The receptor tyrosine kinase inhibitor (RTKI) sunitinib is front-line therapy for metastatic mCC (mRCC), yet all patients eventually become resistant to this anti-angiogenic drug. Unlike other RTKIs, sunitinib also prevents RCC-induced accumulation of myeloid derived suppressor cells (MDSC) and normalizes type-1 T cell function. We observed that this remarkable immunomodulatory impact occurs both in patients and animals regardless of whether tumors regress, stabilize or progress during sunitinib therapy. Nevertheless, critical issues remain to be addressed before sunitinib can reach its full therapeutic potential as an immunomodulator, including the capacity of intratumoral MDSC to resist sunitinib, as well as sunitinib´s capacity to inhibit dendritic cell (DC) in addition to MDSC accumulation.. The proposed studies will employ several murine tumor models as well as blood and tumor samples from stage IV mRCC patients to investigate sunitinib´s immunotherapeutic impacts in both mouse and cancer patients. Aim 1 will delineate the mechanisms by which sunitinib prevents tumor enhancement of monocytic-MDSC proliferation, neutrophilic-MDSC differentiation, and neutrophilic-MDSC survival. Aim 1 will also explore the likelihood that sunitinib´s blockade of these three steps of MDSC development is the consequence of promiscuous targeting of different RTKs at each step. Aim 2 will test the mechanism(s) by which MDSC in tumor and bone marrow compartments display distinctive resistance to sunitinib, contrasting to the extreme sunitinib susceptibility observed for MDSC in peripheral compartments such as spleen and blood.. We have tentatively correlated such sunitinib resistance to locally heightened exposure to GM-CSF and/or hypoxia which causes bystander MDSC to develop in a STAT3-independent manner, thus promoting sunitinib resistance and local T cell dysfunction. Aim 3 will investigate how sunitinib´s capacity to inhibit DC as well as MDSC accumulation impacts its use as an immunomodulator in the setting of vaccine and adoptive T cell immunotherapy. We will develop and test immunotherapy strategies which effectively compensate for sunitinib-induced host DC depletion, and which also aim to overcome compartmental MDSC resistance to sunitinib. These studies should provide the necessary mechanistic and technical insights to pave a clear path for future clinical trials that optimize sunitinib´s use in combination immunotherapy for multliple tumor types, including those which may not be angiogenically susceptible to sunitinib therapy This study is an extension of our observation that the anti-angiogenic drug sunitinib (Sutent), which is active in the treatment of kidney cancer, also boosts the immune system by inhibiting cells called myeloid-derived suppressor cells (MDSC). These studies will aim to understand exactly how sunitinib causes improvements in the anti-cancer immune response, how to make sunitinib even more effective against cancers, and how to make sure the immune system is working at its best during sunitinib treatment
Keywords: Address; adenocarcinoma of kidney; Adenocarcinoma, Renal Cell; adoptive cell immunotherapy; Adoptive Cellular Immunotherapy; Adoptive Immunotherapy; Angiogenesis Antagonists; Angiogenesis Blockers; Angiogenesis Inhibitors; Angiogenetic Antagonists; Angiogenic Antagonists; Angiostatic Agents; Animals; Anti-Angiogenetic Agents; Anti-Angiogenic Agents; Anti-Angiogenic Drugs; Antiangiogenesis Agents; antiangiogenic; Antiangiogenic Agents; BAY 43-9006 tosylate (BAY 54-9085); BAY 43-9006 Tosylate Salt; BAY 54-9085; biological signal transduction; Blood; Blood monocyte; body system, allergic/immunologic; Bone Marrow Neoplasms; Bone Marrow Tumor; c kit; c-kit Protein; c-kit Receptor; cancer immunotherapy; Cancer Patient; cancer type; Cancers; Carcinoma, Hypernephroid; CD117 Antigens; Cell Communication and Signaling; Cell Differentiation; Cell Differentiation process; Cell Function; Cell Growth in Number; Cell Multiplication; Cell physiology; Cell Process; Cell Proliferation; Cell Signaling; Cell Survival; Cell Viability; Cells; Cellular Function; Cellular Physiology; Cellular Process; Cellular Proliferation; clinical investigation; Clinical Trials; Clinical Trials, Unspecified; Commit; Complex; Data; Dendritic Cells; depressed; Depressed mood; Development; Dose; drug/agent; Drugs; Dysfunction; Elements; experience; Exposure to; FDA approved; Functional disorder; Future; Generations; GM-CSF; GMCSF; granulocyte macrophage colony stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor; Grawitz Tumor; Health; healthy volunteer; Histamine-Producing Cell-Stimulating Factor; host response; Human; Human, General; Hypernephroma; Hypoxia; Hypoxic; Imatinib; immune adjuvant; Immune response; Immune system; immune therapy; Immuno-Chemotherapy; Immunoactivators; Immunoadjuvants; Immunochemotherapy; Immunologic Adjuvants; immunologic preparation; Immunological Adjuvant; Immunologically Directed Therapy; Immunomodulators; Immunopotentiators; immunoresponse; Immunostimulants; Immunotherapeutic agent; immunotherapeutics; Immunotherapy; Immunotherapy, Adoptive; Immunotherapy, Cancer, General; In Vitro; Individual; inhibitor; inhibitor/antagonist; Inhibitors, Angiogenetic; Inhibitors, Angiogenic; insight; Intracellular Communication and Signaling; ITX; Kidney Cancer; Kidney Carcinoma; kit Proto-Oncogene Protein; Location; malignancy; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; Man (Taxonomy); Man, Modern; Marrow monocyte; Mast Cell Growth Factor Receptor; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; Mediating; Medication; Mice; Modeling; Molgramostin; monocyte; Murine; Mus; Myelogenous; Myeloid; neoplasm/cancer; Neovascularization Inhibitors; Nephroid Carcinoma; new therapeutics; next generation; next generation therapeutics; novel therapeutics; organ system, allergic/immunologic; Oxygen Deficiency; p145(c-kit); p145c-kit; pathophysiology; Patients; Peripheral; peripheral blood; Pharmaceutic Preparations; Pharmaceutical Preparations; Physiopathology; pre-clinical; preclinical; Predisposition; prevent; preventing; Production; Property; Property, LOINC Axis 2; Protein Tyrosine Kinase Inhibitors; Proto-Oncogene Protein c-kit; PTK Inhibitors; receptor; Receptor Protein; Renal Adenocarcinoma; Renal Cancer; Renal carcinoma; Renal Cell Cancer; Renal Cell Carcinoma; Renal Cell Carcinoma, Stage Unspecified; Resistance; resistant; response; Reticuloendothelial System, Blood; Reticuloendothelial System, Spleen; Role; sadness; Sampling; SCF Receptor; Signal Transduction; Signal Transduction Systems; Signaling; social role; Sorafenib; Spleen; Staging; STAT3; STAT3 gene; Stem Cell Factor Receptor; Subcellular Process; Suppressor Cells; suppressor T lymphocyte; Suppressor-Effector T-Lymphocytes; Susceptibility; Sutent; T cell response; T Suppressor Cell; T-Cell Activation; T-Cells; T-Cells, Suppressor-Effector; T-Lymphocyte; T-Lymphocytes, Suppressor-Effector; TC-GM-CSF; Testing; Therapeutic; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; TK Inhibitors; tumor; Tumor-Cell Human GM Colony-Stimulating Factor; Tyrosine Kinase Inhibitor; Vaccines; Veiled Cells; Work
Relevance: This study is an extension of our observation that the anti-angiogenic drug sunitinib (Sutent), which is active in the treatment of kidney cancer, also boosts the immune system by inhibiting cells called myeloid-derived suppressor cells (MDSC). These studies will aim to understand exactly how sunitinib causes improvements in the anti-cancer immune response, how to make sunitinib even more effective against cancers, and how to make sure the immune system is working at its best during sunitinib treatment
Project start date: 2010-08-01
Project end date: 2015-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-070
5R01CA150959-02 (2011): $524381
MECHANISMS OF DE NOVO METHYLATION IN CANCER
A Peter, Professor
University Of Southern Californiacity: Los Angeles country: United States (us)
Grant 5R37CA082422-13 from National Cancer Institute
Abstract: The objectives of this grant, which has been funded for almost 30 years, have been to understand the mechanisms for the establishment and inheritance of DNA methylation patterns and to develop drugs which can interfere with cytosine methylation and reactivate silenced genes. This research has led to the recent approval by the FDA of two DNA demethylating agents (5-aza-CR and 5-aza-CdR) for the treatment of myeloid dysplastic syndrome. In the next five year period of the project, we hope to take advantage of epigenomic analysis to understand how DNA methylation patterns are established and maintained by an interaction between DNA methyltransferases and specific chromatin components. To do this, we have developed a custom NimbleGen array allowing for the analyses of nucleosomes, histone modifications and DNA methylation in an integrated way at 1,800 transcription start sites (TSS) in normal and transformed cells. In Specific Aim 1, we will utilize the tiling array to map nucleosomes in both normal (PrECs) and transformed prostate cancer cells (PC3). We shall then determine how interfering with DNA methylation pharmacologically in PC3 cells or genetically in HCT116 colon cancer cells alters the distribution of histone marks focusing on the histone H3-K27me3 mark applied by the polycomb repressive complex 2 (PRC2). In Specific Aim 2, we shall determine how the epigenome is reorganized during the restoration of DNA methylation to HCT116 derivatives (DKO) in which two of the three DNA methyltransferases (DNMT1 and DNMT3B) have been genetically knocked down. In Specific Aim 3, we will follow-up on our new results which show the strong anchoring of the de novo methyltransferases DNMT3A and 3B to nucleosomes. We wish to determine how the enzymes interact with nucleosomes so that we can understand how specific patterns are established. In Specific Aim 4, we will continue our quest to develop DNA demethylating drugs which are more stable than those currently approved by the FDA for cancer treatment and which are able to reverse aberrant DNA methylation, histone modifications and nucleosome positioning. Achievement of these aims should have major impact in our understanding of the epigenetics of cancer and have direct relevance to new strategies to treat and prevent cancer. It has become clear over the last few years that the abnormal silencing of genes by somatically heritable epigenetic processes, can contribute directly to the formation of human cancers. Although we know that altered patterns of DNA methylation play a fundamental role in the silencing of tumor suppressor genes, we do not know how these altered patterns are set up or how normal patterns are established and inherited during human development. Recent excitement in the field has focused on the potential role of gene silencing mechanisms involving the polycomb repressive complexes (PRCs), which are essential for normal development and have recently been found also to play a role in inactivating tumor suppressor genes. These PRCs can directly silence genes by themselves and also somehow set up genes for more permanent silencing induced by DNA methylation. Recently, the FDA has approved two DNA demethylating agents and one histone deacetylase inhibitor for the treatment of particular kinds of cancer
Keywords: Aberrant DNA Methylation; Achievement; Address; Azacitidine; Biochemical; cancer cell; cancer therapy; cell transformation; Cells; Chromatin; chromatin protein; Colon Carcinoma; Complex; CpG Islands; Custom; Cytosine; Deamination; density; Deoxycytidine; design; Development; DNA; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; Drug Delivery Systems; Drug Design; Enzymes; Epigenetic Process; epigenomics; FDA approved; follow-up; Funding; Gene Silencing; Genes; Goals; Grant; HCT116 Cells; Health; Histone Deacetylase Inhibitor; Histone H3; histone modification; Histones; Human; Human Development; Hydrolysis; Inherited; inhibitor/antagonist; knock-down; Maintenance; Malignant neoplasm of prostate; Malignant Neoplasms; malignant phenotype; Maps; Methylation; Methyltransferase; Myelogenous; Normal Cell; Nucleosomes; Patients; Pattern; Pharmaceutical Preparations; Play; Polycomb; Positioning Attribute; prevent; Process; Relative (related person); Research; research study; restoration; Role; Somatic Cell; Syndrome; Testing; Transcription Initiation Site; Tumor Suppressor Genes; Universities
Project start date: 1999-09-17
Project end date: 2014-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R37CA082422-13 (2011): $421735
DE NOVO DNA METHYLATION IN BLADDER CANCER
A Peter, Professor
University Of Southern Californiacity: Los Angeles country: United States (us)
Grant 5R01CA083867-12 from National Cancer Institute
Abstract: The objectives of this grant, which has been funded for almost 30 years, are to understand the genetic and epigenetic basis of human bladder cancer. We have defined the existence of two molecular pathways for the genesis of bladder cancer (UC) in which superficial (Ta/T1) tumors, which frequently recur, are distinct from more aggressive tumors at the molecular level. We have also shown profound epigenetic alterations which occur during bladder carcinogenesis and want to continue our studies by using more global approaches to define key genes which may play a role in this prevalent but understudied disease. In the next five year period of the grant, we will use a series of eight hypermethylation markers to complete the examination of DNA in urine sediments obtained from individuals with low grade tumors to determine whether we can detect the frequent recurrences of these tumors. We shall also complete the analysis of DNA from healthy individuals of different ages to determine whether age-related changes in DNA methylation can be detected in urine sediments. Secondly, using high-throughput approaches on the Illumina platform, we have observed a hypomethylation phenotype not seen in the apparently normal urothelium but particularly prevalent in superficial tumors and less frequently in more invasive tumors. This hypomethylation is seen in the vicinity of transcription start sites and might play a role in ectopic gene activation in tumors. In Specific Aims 3 and 4 we will determine the functional significance of these changes by analyzing directly whether methylation of non- CpG island regions which constitute the bulk of the hypomethylation phenotype might be involved in gene activation and have chromatin properties associated with active genes. Finally, in Specific Aim 5 we will take advantage of ongoing clinical trials in which patients with myelodysplastic syndrome are being treated with the hypomethylating drug 5-azacytidine (5-aza-CR). Since we can easily and non-invasively obtain urine sediments from these patients, we can directly test the hypothesis that systemic administration of hypomethylating drugs leads to demethylation of bladder urothelial cells which may have implications in the future for treatment of this disease. Bladder cancer is the 5th most common cancer in the United States and is one of the most expensive cancers to treat because of its propensity to recur. We have discovered substantial epigenomic changes in low grade (Ta/T1) tumors which can be detected in urine sediments and might help steer clinical decisions associated with gene activation in the tumors, and shall investigate the mechanism for this action. We want eventually to develop epigenetic therapies for bladder cancer and shall take advantage of clinical trials in which patients who do not have this disease are being treated with demethylating agents to test the effects of these drugs on DNA methylation patterns in the normal urothelial cells of humans
Keywords: Aftercare; Age; age group; age related; Azacitidine; base; Bladder; bladder Carcinoma; Bladder Neoplasm; Bladder Urothelial Cell; Cancer Patient; carcinogenesis; Cell Line; cell transformation; Cells; Chromatin; chromatin modification; Chromatin Structure; Clinical; Clinical Trials; CpG Islands; Cultured Tumor Cells; Data; demethylation; Diagnostic Neoplasm Staging; Disease; DNA; DNA analysis; DNA Methylation; Dysmyelopoietic Syndromes; Epigenetic Process; epigenomics; Etiology; FDA approved; Funding; Future; Gene Activation; Gene Expression; Gene Silencing; Genes; Genetic; Genomics; Goals; Grant; Histones; Human; Hypermethylation; Individual; inhibitor/antagonist; Island; Lead; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Malignant Neoplasms; Maps; Measures; Methylation; Methyltransferase; Molecular; normal aging; Normal Cell; Nucleosides; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Play; Positioning Attribute; Promotor (Genetics); Property; public health relevance; Recurrence; Repetitive Sequence; Role; Sampling; Series; Site; Staging; Techniques; Testing; Time; Transcription Initiation Site; Transurethral Resection; tumor; Tumor stage; ultra high resolution; United States; Urine; Urothelial Cell; Urothelium; Variant; Work
Project start date: 2000-03-01
Project end date: 2015-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01CA083867-12 (2011): $272325
A Peter, Co-director, Ucla Ibd Center
University Of California Los Angelescity: Los Angeles country: United States (us)
Abstract: The Mucosal Immunology Core Laboratory (MICL) was first proposed and funded in 1998 due to an emerging awareness that mucosal lymphoid tissues were critically important as a reservoir for HIV infection. To our knowledge, this was the first Core facility of its kind in CFAR and continues to be a unique resource nationally. Interested researchers had little access to freshly acquired tissue and there were no validated assays for quantifying tissue HIV viral burden as well as other relevant mucosal immunologic and virologic markers. Since the start of the most recent CFAR renewal 4.5 years ago, the MICL has collected over 8000 mucosal tissue biopsies for study from 362 subjects. An additional 407 MICL encounters include 235 subject visits for screening, blood or semen donation without biopsies and 172 tissue specimens received from collaborators for assays or tissue specimens received from the Tissue Procurement Core Laboratory (TPCL). Also the MICL has supported 21 researchers (8 non-UCLA), 21 grant applications (16 funded), and during the past 2 years the MICL has developed a Clinical Trial Registry of 317 potential subjects for proactive recruitment as needed. This resource in unmatched anywhere and is a very unique CFAR resource for HIV investigators
Keywords: Acquired Immunodeficiency Syndrome; Advertisements; AIDS prevention; Applications Grants; Area; Awareness; Biological Assay; Biopsy; Biostatistics Core; Blood; Blood Screening; Blood specimen; Books; Cells; Cervix Uteri; chemokine; Clinical; Clinical Trials; cohort; Colon; Communities; Consent Forms; Consult; Consultations; Core Facility; cytokine; Development; DNA; Epithelium; Fostering; Funding; Gastroenterology; gastrointestinal; Gastrointestinal tract structure; Goals; Grant; HIV; HIV Infections; Human; Immune response; Immunologics; Immunology; Infection; innovation; Institutes; Institutional Review Boards; interest; investigator training; Laboratories; Link; Lymphocyte; Lymphoid Tissue; microbicide; Minority; Mononuclear; mucosal site; Mucous Membrane; novel; Operative Surgical Procedures; Pathogenesis; Patient Selection; Patients; Preparation; Process; Psychological Transfer; Quality Control; Recruitment Activity; rectum/anus; Registries; relational database; Research; Research Design; Research Personnel; research study; Resources; RNA; sample collection; Sampling; Seminal fluid; Services; Site; Small Intestines; Specimen; Stomach; Suspension substance; Suspensions; Techniques; Technology; Technology Transfer; Testing; Time; Tissue Procurements; Tissue Sample; Tissues; Tonsil; treatment response; treatment strategy; United States National Institutes of Health; Vaccines; Validation; Viral Load result; virology; Visit; Woman
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
5P30AI028697-22_9025 (2011): $126429
INNATE AND ADAPTIVE IMMUNITY IN EXPERIMENTAL AND HUMAN GONOCCOCAL INFECTION
A Peter, Professor Of Medicine
Univ Of Massachusetts Med Sch Worcestercity: Worcester country: United States (us)
Grant 5U19AI084048-03 from National Institute Of Allergy And Infectious Diseases
Abstract: The major objectives of this Sexually Transmitted Infections Co-operative Research Center (STI-CRC) entitled "Innate and Adaptive Immunity in Experimental and Human Gonococcal Infection in Women" are directed to providing a diverse and comprehensive understanding of the innate and adaptive immune mechanisms associated with gonococcal infection. We will emphasize basic host responses and innate immune mechanisms in infection with Neisseria gonorrhoeae with the immediate aim of improving understanding of gonococcal immunology and pathogenesis and a longer term goal to gain insights that will direct efforts to facilitate the prevention of gonococcal infections in humans, particularly women. We will use a promising animal model to examine these mechanisms and separately employ a generalized translational approach that will emphasize the links between immunobiology and clinical epidemiology to assess the potential of vaccine candidates in humans, which will then be investigated in the context of the humanized mouse model of infection. Five research projects and four service cores are proposed. In the first project (Douglas T Golenbock, MD, PL), we will address a basic and fundamental question in lipopolysaccharide (LPS, called lipooligosaccharide [LOS] in the case of N. gonorrhoeae) biology to understand the binding of LOS derived lipid A with its direct ligand that serves as an intermediary structure to activate and permit signaling of toll-like receptor (TLR)4. In Project 2 (Robin Ingalls, MD, PL), we will determine if naturally occurring mutations in gonococcal LOS or polymorphisms in the TLR4 adaptor Mai, account for differences in the host inflammatory response to infection. In Project 3 (Caroline A Genco, PhD, PL), we will examine the role that TLRs and cytosolic nucleotide oligomerization domain (NOD) protein receptors (NOD-like receptors [NLRs]) play as receptors for Neisseria ligands. In Project 4 (Sanjay Ram, MD, PL), we will examine novel roles for the alternative complement pathway (ACP) enhancing molecule. Properdin, in blocking TLR4 mediated signaling by LOS and separately, in amplifying potentially protective vaccine induced antibody function. In Project 5 (Peter A. Rice, MD), we will examine peptide mimics of gonococcal LOS as potential vaccine candidates in a humanized mouse model of gonococcal infection while also determining if natural antibodies against the candidates protect exposed women from gonococcal infection. The Center will have five Cores (Clinical, Laboratory, Animal Statistical, and administrative) providing support to 4 or 5 of the 5 Projects
Relevance: Gonorrhea is a common sexually transmitted infection worldwide. Women usually have few or no symptoms associated with infection, which often leads to delays in treatment and the development of complications such as pelvic inflammatory disease and infertility and increased likelihood of acquiring HIV infection. A better understanding of natural immunity to this pathogen will lead to treatments that can lessen the infectious complications and support the development of protective vaccine strategies
Project start date: 2009-09-25
Project end date: 2014-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-AI-08-004
5U19AI084048-03 (2011): $2574877
IDENTIFICATION OF GENES ACTIVATED BY BILE ACIDS
A Peter, Professor Of Biological Chemistry & Medi
University Of California Los Angelescity: Los Angeles country: United States (us)
Grant 5R01HL068445-09 from National Heart, Lung, And Blood Institute
Abstract: The major goals of our research have been to identify the mechanisms of activation of the farnesoid X receptor (FXR) and to define its role in regulating metabolic pathways. To this end, we have identified four human and murine FXR transcripts derived from a single gene that encode four different protein isoforms. Our identification of a four amino acid motif (MYTG), located immediately adjacent to the DNA binding domain of two of the four isoforms, dramatically altered our thinking about this transcription factor; new and exciting data suggest that the presence of this motif affects transactivation of certain hepatic and adrenal genes. We have recently discovered that activated FXR has a pronounced effect on glucose metabolism in mice and is highly protective against the acute hepatoxicity produced by toxic xenobiotics and from the toxic effects of IPS (lipopolysaccharide). We have also recently obtained evidence that FXR regulates a number of steroidogenic genes, suggesting a functional role for FXR in the adrenal cortex. Based on these data, generated during the current grant period, we propose to conduct mechanistic studies to elucidate the roles of FXR in i) the control of plasma glucose levels and hepatic glucose metabolism, ii) the control of plasma and hepatic lipid levels, iii) protection of the liver from damage induced by xenobiotics such as acetaminophen, iv) protecting mice from endotoxin shock and bacterial infection and v) the regulation of target genes in adrenal steroidogenic cells. These studies will be aided by the availability of FXR transgenic and FXR-/- mice, and mice lacking FXR in the liver or intestine, and adenovirus expressing individual FXR isoforms. To complement these approaches, mechanistic studies will be conducted to elucidate the function of the MYTG motif present in two of the four FXR isoforms. Taken together, these studies will identify novel regulatory mechanisms by which FXR isoforms activate transcription. In addition, these studies will elucidate the role of FXR in glucose, steroid and drug metabolism and in resistance to endotoxin
Keywords: Acetamide, N-(4-hydroxyphenyl)-; Acetamidophenol; Acetaminophen; Acetominophen; Acute; Adenoviridae; Adenoviruses; Adrenal Carcinoma; Adrenal Cortex; Adrenal Gland Carcinoma; Adrenal Glands; Adrenals; ADRGND; Affect; Amino Acid Motifs; APAP; Autoregulation; Bacteria; bacterial disease; Bacterial Infections; base; Bile Acids; Binding; Binding (Molecular Function); blood glucose regulation; Blood Plasma; body system, hepatic; bowel; Cells; ChIP (chromatin immunoprecipitation); CHIP assay; chromatin immunoprecipitation; Circulatory Collapse; circulatory shock; Complement; Complement Proteins; Cortex of adrenal gland; D-Glucose; Data; Dextrose; DNA Binding Domain; drug metabolism; Endotoxins; experiment; experimental research; experimental study; farnesoid X-activated receptor; FX receptor; FXR protein; Gene Action Regulation; Gene Expression; Gene Expression Regulation; gene product; Gene Regulation; Gene Regulation Process; Gene Targeting; Gene Transcription; Genes; Genetic Transcription; Glucose; glucose control; glucose homeostasis; glucose metabolism; glucose regulation; Goals; Gram-Positive Bacteria; Grant; Hepatic; Hepatic Failure; Hepatotoxic effect; Hepatotoxicity; hepatoxicity; Homeostasis; host response; Human; Human, General; Hydroxyacetanilide; Hypoglycemia; hypoglycemic; hypoglycemic episodes; hypolipidemia; Immune response; immunoresponse; in vivo; Individual; Infectious Agent; infectious organism; Injury; Intestinal; Intestines; Isoforms; Ligands; Lipids; Lipopolysaccharides; Liver; Liver Failure; Liver Toxicity; LPS; Mammals, Mice; Man (Taxonomy); Man, Modern; Metabolic Pathway; Mice; Modeling; Molecular Interaction; Murine; Mus; N-(4-Hydroxyphenyl)acetanilide; N-Acetyl-p-aminophenol; novel; NRIH4 protein; organ system, hepatic; oxidation; p-Acetamidophenol; p-Hydroxyacetanilide; Paracetamol; pathway; Pathway interactions; Phosphorylation; Physiological Homeostasis; Plasma; Post-Translational Modification Site; Process; protective effect; Protein Isoforms; Protein Motifs; Protein Motifs, DNA-Binding; Protein Phosphorylation; Proteins; receptor; Receptor Activation; Receptor Protein; Regulation; Relative; Relative (related person); Research; research study; Resistance; resistant; Response Elements; Reticuloendothelial System, Serum, Plasma; RNA Expression; Role; Septic Shock; Serum, Plasma; Shock; social role; Steroid Compound; Steroids; suprarenal gland; Targetings, Gene; Testing; Thinking; Thinking, function; Toxic effect; Toxic effect on liver cells; Toxicities; Trans-Activation (Genetics); Transactivation; Transcript; Transcription; Transcription Activation; transcription factor; Transcription, Genetic; Transcriptional Activation; transgenic; Transgenic Organisms; Up-Regulation; Xenobiotics
Project start date: 2001-09-01
Project end date: 2011-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2011
5R01HL068445-09 (2009): $366235
ACOUSTO-OPTIC THERAGNOSTIC APPROACH FOR CHRONIC WOUND MANAGEMENT
A Peter
Drexel Universitycity: Philadelphia country: United States (us)
Grant 5R01EB009670-02 from National Institute Of Biomedical Imaging And Bioengineering
Abstract: The long-term objective of our proposed program is to develop a non-invasive chronic wound treatment that combines optic and acoustic modalities in a synergistic way. This theragnostic, i.e. thera(peutic) and (dia)gnostic technology, merging a non-invasive ultrasound therapy with Near Infrared (NIR) diagnostic monitoring, will allow a wound care provider to prescribe low frequency ultrasound therapy through a "Band-Aid(R)"-like wearable patch, assess the status of wound healing with digital imaging and NIR, and adjust the ultrasound parameters as necessary. The treatment considered here involves exposure of the wound to non-invasive low (20-100 kHz) frequency ultrasound energy with periodic real-time digital and near infrared (NIR) monitoring of tissue optical properties related to wound healing parameters. Thus, in vivo acquired diagnostic information provided by an optic sensor will be combined with therapy and used to direct and optimize wound healing treatment. Our ultimate goal is to develop a sterile, patient friendly patch containing an ultrasound applicator and associated electronic controls that could be directly applied by a patient to the wound. This wearable patch will allow for frequent (daily or even multiple exposures per day) application of the ultrasound therapy without a return of the patient to the clinic and will significantly increase patient compliance with the therapy. In order to accomplish this goal, we will establish the optimal ultrasound exposure parameters that will serve as the basis for the prototype "Band-Aid(R)"-like wearable ultrasound applicator. The novelty of our approach consists of using non-invasive, safe levels of low frequency ultrasound therapy with non-invasive optical diagnosis of wound healing enabled through the unique development of a low-cost wearable ultrasound applicator. This systematic approach will be validated through a study of venous ulcers in humans, providing quantitative information not available currently. Our underlying hypothesis is that low frequency ultrasound can provide an effective therapy for chronic wounds and that application of this therapy can be optimized by assessment of wound healing through NIR monitoring. Accordingly, our specific aims are Specific Aim 1 Develop optimal exposure matrix protocol for ultrasonically assisted chronic wound healing. Identify optimal ultrasound "low" frequency (20 or 100kHz) and assess effect of total energy density on wound healing. Wound healing is assessed by NIR and wound size determination. Specific Aim 2 Based on the outcomes of Specific Aim 1, develop and test an early prototype of the "Band-Aid(R)"-like wearable ultrasound patch device based chronic wound ultrasound applicator. Specific Aim 3 Using the prototype of the ultrasound applicator developed in Specific Aim 2 identify the possible role of (inertial and stable) cavitation and mechanical stresses as possible mechanisms, and rule out thermal effects. Specific Aim 4 Validate the "Band-Aid(R)"-like wearable ultrasound patch prototype in human patients under the optimal conditions identified in Specific Aim 1. At the completion of this research, the optimum exposure matrix will be established and an early prototype of the wearable chronic wound applicator will be constructed and tested. The results of this project will also provide insights into the possible mechanisms affecting wound healing. Chronic wounds, which include venous leg ulcers, pressure sores, ischemic ulcers, and diabetic foot ulcers, are a significant problem in today´s aging society. In the United States there are over 4 million patients afflicted with these types of wounds, with an annual treatment cost of 9 billion dollars. The proposed theragnostic technology, merging wearable non-invasive low frequency ultrasound therapy with near infrared diagnostic monitoring, can result in a customized treatment modality which has the potential to deliver individualized effective therapy at low cost
Keywords: absorption; Acoustics; Affect; Aging; Animal Model; Animals; base; Care given by nurses; Caring; Cell membrane; Chronic; Clinic; Clinical; Combined Modality Therapy; Compliance behavior; Computers; cost; Decubitus ulcer; design; Development; Devices; Diabetic Foot Ulcer; Diagnosis; Diagnostic; digital; digital imaging; effective therapy; Electronics; energy density; Evaluation; Fiber; Frequencies (time pattern); Goals; Guidelines; Healed; healing; Health Personnel; Hospitals; Human; human study; human subject; in vitro testing; in vivo; insight; Investigation; laptop; Left; Leg Ulcer; Measurement; Measures; Mechanical Stress; Methodology; Methods; miniaturize; Modality; Molecular; Monitor; Optics; Outcome; Outpatients; Patients; Physicians; programs; Property; Protocols documentation; prototype; Provider; public health relevance; Radiation; Reporting; Research; research study; Role; sensor; Societies; Sterility; Stream; Structure; System; Technology; Testing; Time; TimeLine; Tissues; Transducers; Treatment Cost; Ulcer; Ultrasonic Therapy; Ultrasonography; United States; Variant; Varicose Ulcer; Venous; Visit; Visual impairment; Work; wound; Wound Healing
Relevance: Relevance Chronic wounds, which include venous leg ulcers, pressure sores, ischemic ulcers, and diabetic foot ulcers, are a significant problem in today´s aging society. In the United States there are over 4 million patients afflicted with these types of wounds, with an annual treatment cost of 9 billion dollars. The proposed theragnostic technology, merging wearable non-invasive low frequency ultrasound therapy with near infrared diagnostic monitoring, can result in a customized treatment modality which has the potential to deliver individualized effective therapy at low cost
Project start date: 2010-05-01
Project end date: 2014-02-28
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01EB009670-02 (2011): $478254
EBP50 REGULATION OF PTH RECEPTOR IN BONE
A Peter, Professor
University Of Pittsburgh At Pittsburghcity: Pittsburgh country: United States (us)
Grant 2R01DK069998-06 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The long-term goal of this project is to elucidate the cellular mechanisms by which the 50-kDa ezrin-bind protein (EBP50) regulates parathyroid hormone receptor (PTHR)-mediated signaling and function in bone. Mice with targeted deletion of EBP50 exhibit a bone phenotype, as do patients with EBP50 mutations. Although it is thought that the bone disorder arises as a secondary consequence of renal dysfunction, our preliminary data identify direct effects of EBP50 on bone. This suggested a novel mechanism by which mutations interfere with EBP50 function and, by extension, that EBP50 is dynamically regulated by PTH in open and closed conformations. The unifying idea of the present proposal is that novel structural determinants in EBP50 and their posttranslational modification dictate EBP50 function on PTHR activity in bone. Three specific aims are developed to test this idea. In Aim 1 we will characterize EBP50 conformations and dimerization to test the hypothesis that the described mutations lock EBP50 in a closed configuration that interferes with PTHR function. These experiments will use molecular biological maneuvers to examine static interactions, molecular modeling to predict the effect of amino acid mutation on binding affinity, and biophysical measurements of fluorescence resonance energy transfer microscopy to acquire dynamic interactions in living cells and in real time, and surface plasmon resonance to quantify protein-protein interactions. Aim 2 will define post- translational modifications of EBP50 that determine its function. This will be accomplished by testing the hypothesis that PTH-induced phosphorylation of EBP50 induces the closed configuration. We will apply mass spectrometry to identify site-specific EBP50 phosphorylation, and molecular biological tools with phospho-mimics and phospho-resistant EBP50 derivatives to determine their structural conformation and their actions on bone cells. Aim 3 will delineate the direct effects of EBP50 on bone to test the hypothesis that EBP50 regulates bone development and turnover. Several approaches will be applied including allograft transplantation to determine if the bone phenotype of EBP50-null mice can be rescued by transplanting marrow stem cells from wild-type mice. Other experiments will involve transfecting bone cell models with mutant EBP50 or EBP50 harboring phospho-mimics or phospho- resistant forms of EBP50 to determine how these influence PTHR action. These studies will quantitatively examine the relations between EBP50 structure and function and characterize a novel mechanism to explain the regulation and origin of EBP50 effects on bone. The findings will generate new information that is relevant to understanding bone turnover. The outcomes will help define potential therapeutic targets for improved treatment of osteoporosis and other metabolic bone diseases. The proposed studies will test how the adapter protein EBP50 regulates parathyroid hormone action on bone. Patients with EBP50 mutations and mice lacking EBP50 have decreased bone mineral (osteomalacia). Our preliminary studies show that this results from direct effects of EBP50 in bone and not indirectly from loss of phosphate in the urine, as thought. The actions and mechanism by which EBP50 affects bone is not understood. The planned experiments will fill this gap. The outcome of our studies is highly relevant to understanding bone biology and the factors that cause osteomalacia, osteopenia, osteoporosis, and other related bone disease. The results will help define potential therapeutic targets for improved treatment of osteoporosis and other metabolic bone diseases
Keywords: Accounting; adapter protein; Adenosine Cyclic Monophosphate-Dependent Protein Kinases; Affect; Affinity; Allografting; Amino Acids; aminoacid; Award; balance; balance function; base; Bears; Binding; Binding (Molecular Function); Binding Proteins; Biochemical; Biological; Biology; bone; Bone; Bone and Bones; bone cell; Bone Development; Bone Diseases; Bone Diseases, Metabolic; bone disorder; Bone Marrow Transplant; Bone Marrow Transplantation; bone mass; bone metabolism disorder; Bone Sarcoma; bone turnover; Bones and Bone Tissue; cAMP-Dependent Protein Kinases; Cell model; Cells; Cellular model; conformation; conformational state; Cyclic AMP-Dependent Protein Kinases; Data; Dimerization; Drosophila; Drosophila genus; Dysfunction; Engineering; Engineerings; Equilibrium; Exhibits; experiment; experimental research; experimental study; ezrin; Fluorescence Resonance Energy Transfer; FRET; fruit fly; Fruit Fly, Drosophila; Functional disorder; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Goals; Grafting, Bone Marrow; heavy metal lead; heavy metal Pb; hPTH(1-84); Human; human PTH protein; Human, General; improved; In element; Indium; inorganic phosphate; Intermediary Metabolism; Ions; Kidney; Knockout Mice; L-Serine; Lead; Life; Ligand Binding Protein; Light; Mammals, Mice; Man (Taxonomy); Man, Modern; Marrow; Marrow Transplantation; Mass Spectrum; Mass Spectrum Analysis; Measurement; Measures; Mediating; metabolic bone disease; Metabolic Bone Diseases; Metabolic disorder of bone; Metabolic Processes; Metabolism; METBL; Method LOINC Axis 6; Methodology; Mice; Mice, Knock-out; Mice, Knockout; Microscopy; Minerals; Modeling; Molecular; Molecular Configuration; Molecular Conformation; Molecular Interaction; molecular modeling; Molecular Models; Molecular Stereochemistry; Molecular Target; Mother Cells; Murine; Mus; mutant; Mutation; novel; Nucleic Acid Biochemistry, Molecular Modeling; Null Mouse; Osseous Sarcoma; Osteoblasts; osteochondrosarcoma; osteoid sarcoma; Osteomalacia; Osteopenia; Osteoporosis; osteosarcoma; Outcome; parathormone; Parathyroid Hormone; Parathyroid Hormone (1-84); Parathyroid Hormone Receptor; Parathyroid Hormone Receptor 1; Parathyroid Hormone Receptor Type I; Parathyroid Hormone Receptors; parathyroid hormone, human; Parathyroid Hormone-Related Peptide Receptor; Parathyroid Hormones; pathophysiology; Patients; Pb element; Phenotype; Phosphates; phosphoprotein p81; Phosphorylation; Photometry/Spectrum Analysis, Mass; Photoradiation; Physiopathology; Pilot Projects; pilot study; PKA; Post-Translational Modifications; Post-Translational Protein Processing; Posttranslational Modifications; prevent; preventing; Progenitor Cells; Protein Dimerization; Protein Kinase A; Protein Modification; Protein Modification, Post-Translational; Protein Phosphorylation; Protein Processing, Post-Translational; Protein Processing, Posttranslational; protein protein interaction; Protein/Amino Acid Biochemistry, Molecular Modeling; Protein/Amino Acid Biochemistry, Post-Translational Modification; PTH (1-84); PTH protein, human; PTH-PTHrP Receptor; PTH-Related Peptide Receptor; PTH-Related Protein Receptor; PTHLP Receptor; PTHrP Receptor; public health relevance; receptor; receptor binding; receptor function; Receptor Protein; Receptor Signaling; Receptor, Parathyroid Hormone, Type 1; Receptor, Parathyroid Hormone-Like Peptide; receptor-mediated signaling; Regulation; renal; research study; Resistance; resistant; Rest; Role; Sarcoma, Osteogenic; scaffold; scaffolding; Scaffolding Protein; Serine; Site; skeletal; Skeletal Sarcoma; small molecule; social role; Source; Spectrometry, Mass; Spectroscopy; Spectroscopy, Mass; Spectrum Analyses; Spectrum Analyses, Mass; Spectrum Analysis; Spectrum Analysis, Mass; Stem cells; Structure; Surface Plasmon Resonance; Testing; therapeutic target; Time; tool; transplant; Transplantation; Urinary System, Kidney; Urinary System, Urine; Urine; Ursidae; Ursidae Family; wasting; Wild Type Mouse; Work
Relevance: The proposed studies will test how the adapter protein EBP50 regulates parathyroid hormone action on bone. Patients with EBP50 mutations and mice lacking EBP50 have decreased bone mineral (osteomalacia). Our preliminary studies show that this results from direct effects of EBP50 in bone and not indirectly from loss of phosphate in the urine, as thought. The actions and mechanism by which EBP50 affects bone is not understood. The planned experiments will fill this gap. The outcome of our studies is highly relevant to understanding bone biology and the factors that cause osteomalacia, osteopenia, osteoporosis, and other related bone disease. The results will help define potential therapeutic targets for improved treatment of osteoporosis and other metabolic bone diseases
Project start date: 2005-01-01
Project end date: 2015-01-31
Budget start date: 22-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-10-067
2R01DK069998-06 (2011): $329513
Sponsored Links Excellgen http://Excellgen.com
A Peter, Professor Of Medicine
Univ Of Massachusetts Med Sch Worcestercity: Worcester country: United States (us)
Abstract: The Administrative Core will support the co-Directors and the administrative staff in the entire project. Bimonthly scientific meetings will be organized and will be held jointly among the University of Massachusetts Medical School (UMass), Boston Medical Center (BMC) and Boston University School of Medicine (BUSM) PDs/Pls (local Executive Committee). A scientific session will follow each business meeting of the local Executive Committee tht will e organized by each PI on a rotating basis. The co-PDs will attend a yeariy meeting held jointly in Washington with other STI CRC PDs that make up the Executive Council. A three person external scientific advisory committee will be formed to advise the Program Directors and to monitor the progress ofthe STI CRC. After reviewing the project, the advisory group will meet with the investigators and provide criticism for each of the projects. An executive session between the advisory group and the Project Directors alone, will follow to review overall strategies and areas where funding readjustments might be appropriate. Administrative assistance will be provided to the three projects and two scientific cores located at UMass, two projects, one core and one sub-core located at BMC/BUSM/BU School of Public Health and the Clinical Core located in Nanjing China
Keywords: adaptive immunity; Advisory Committees; Area; base; Boston; Businesses; China; Clinical; Funding; Human; Infection; Massachusetts; Medical center; medical schools; meetings; Monitor; Natural Immunity; Persons; programs; Public Health Schools; Research Personnel; Universities; Washington
Relevance: The admin core will support the administrative part ofthe entire project
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5U19AI084048-03_6552 (2011): $156250
OXIDATIVE DAMAGE AND CONE CELL DEATH IN RP
A Peter, Professor Of Ophthalmology And Neuroscie
Johns Hopkins Universitycity: Baltimore country: United States (us)
Grant 5R01EY005951-25 from National Eye Institute
Abstract: Several lines of evidence suggest that oxidative damage plays a role in the pathogenesis of age-related macular degeneration (AMD). We hypothesize that oxidative damage also plays an important role in cone cell death in retinitis pigmentosa (RP). If this is true, increased expression of antioxidant enzymes in photoreceptors may be a good therapeutic strategy in both disease processes. In this proposal, we plan to explore the role of the 3 isoforms of superoxide dismutase (SOD) in the oxidative defense system of photoreceptors. To assess the role of endogenous SODs, the effect of deficiency of SOD1 or 3 on photoreceptor survival will be tested in two models of oxidative damage, hyperoxia- and paraquat-induced retinal degeneration. The same two models, along with transgenic and self-complementary adeno- associated viral vector (scAAV)-mediated gene transfer approaches, will be used to test the hypothesis that increased expression of SOD 1, 2, or 3 protects photoreceptors from oxidative damage. The hypothesis that oxidative damage contributes to cone cell death in RP will be tested by determining if increased expression of SOD 1, 2, or 3 reduces cone cell death in two mouse models of RP. The data from all of these experiments in mice will help us to select the appropriate transgene(s) for definitive experiments in a transgenic pig model of RP. In those experiments scAAV-mediated gene transfer of an SOD or combination of SODs will be tested against null vector to determine if increased production of SOD(s) reduces cone cell death. The effects of SOD(s) alone will also be compared to co-expression of SOD(s) with brain-derived neurotrophic factor (BDNF) to determine if the co-expression approach provides additive benefit for cone survival. The major goal of this work is to develop a new gene therapy to promote cone survival in patients with RP. If benefit is demonstrated in preserving cones in patients with RP, a similar strategy could be tested in the future to see if it protects both rods and cones in patients with AMD. This study addresses a major public health problem in the US, inherited retinal degenerations, for which there is currently no effective treatment. In addition, the results may also be applicable to AMD, the most prevalent cause of severe vision loss in Americans over the age of 60
Keywords: 4, 4`-Bipyridinium, 1, 1`-dimethyl-; AAV vector; Address; adeno-associated viral vector; adeno-associated virus vector; Age; Age related macular degeneration; American; Animal Model; Animal Models and Related Studies; anti-oxidant; Antioxidants; BDNF; Blindness; Brain-Derived Neurotrophic Factor; Cell Death; Cessation of life; Cone; cone cell; Cones (Eye); Cones (Retina); cytocuprein; Data; Death; Development; Disease; disease/disorder; Disorder; effective therapy; Enzymes; Erythrocuprein; experiment; experimental research; experimental study; Family suidae; Future; gene therapy; gene therapy clinical trial; Gene Transfer; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; Genetic Intervention; genetic therapy; Goals; Hemocuprein; Hyperoxia; inherited retinal degeneration; Injection of therapeutic agent; Injections; Intervention, Genetic; Isoforms; Knockout Mice; Maculopathy, Age-Related; Mammals, Mice; Mediating; Methyl Viologen; MGC34632; Mice; Mice, Knock-out; Mice, Knockout; MNSOD; model organism; Modeling; Molecular Biology, Gene Therapy; mouse model; Murine; Mus; Mutate; necrocytosis; neurotrophic factor; neurotrophin; neutrophin; novel; Null Mouse; overexpression; oxidative damage; oxygen stress (breathing); Paraquat; Pathogenesis; Patients; Photoreceptor Cell; Photoreceptors; Photoreceptors, Cone; Photoreceptors, Vertebrate; Photosensitive Cell; Pigmentary Retinopathy; Pigs; Play; porcine; Process; Production; Protein Isoforms; Public Health; public health medicine (field); research study; retina degeneration; Retinal Cone; Retinal Degeneration; retinal degenerative; Retinitis Pigmentosa; Rhodopsin; Rod; rod cell; Rod Photoreceptors; Rod-Cone Dystrophy; Rods (Eye); Rods (Retina); Rods and Cones; Role; senile macular disease; social role; SOD; SOD-1 protein; SOD1 gene product; SOD2; SOD2 gene; suid; Suidae; Superoxide Dismutase; superoxide dismutase 1; Superoxide[{..}]superoxide oxidoreductase; Swine; System; System, LOINC Axis 4; Tapetoretinal Degeneration; Testing; Therapeutic; therapeutic target; Therapy, DNA; transfer of a gene; Transgenes; transgenic; Transgenic Organisms; vector; Vertebrate Photoreceptors; Visual Purple; Visual Receptor; Work
Project start date: 1985-09-30
Project end date: 2012-02-29
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
5R01EY005951-25 (2011): $557425
5R01EY005951-24 (2010): $610627
CHEMICAL MODIFICATIONS OF SIRNA BASES TO CONTROL OFF-TARGET EFFECTS
A Peter, Professor
University Of California Daviscity: Davis country: United States (us)
Grant 5R01GM080784-04 from National Institute Of General Medical Sciences
Abstract: Selective nuclease digestion of messenger RNAs inside living cells via the short interfering RNA (siRNA)- triggered RNA interference pathway has become a mainstay in molecular biology to study gene function and holds promise for the development of new therapeutics. However, gaps in our understanding of the basic RNA interference mechanism and the ability of siRNAs to interact with intracellular RNA-binding proteins, particularly those involved in the innate immune response, limit the application of this promising new technology. Here we propose to develop new synthetic approaches to modified RNA oligonucleotides and to use the resulting molecules to carryout gene silencing with reduced undesirable off-target effects. This project has the following specific aims 1) We will synthesize siRNAs bearing pendant alkyl groups projecting into either the major groove or the minor groove. The chemical modifications are designed to change the shape of the base while maintaining its ability to engage in Watson-Crick-like base pairing. These siRNA duplexes will be used to define the effects of nucleobase alkylation in gene silencing. The modifications are also expected to block sequence-dependent off-target effects mediated by Toll-like receptors and sequence- independent off-target effects from dsRBM proteins. 2) We hypothesize that anti-syn conformational changes in modified guanines will act as molecular switches to turn on (when Watson-Crick paired) or off (when Hoogsteen paired) steric blockades in the duplex RNA minor groove. We will investigate two alkylated guanine derivatives as switches, the common oxidized base lesion 8-oxoguanosine (8-oxoG) with added alkyl groups, and the acrolein alkylated purines. These modifications will be placed in the antisense strand using a Watson-Crick-paired sense strand for delivery; the antisense strand will be designed to target a complementary mRNA via Hoogsteen pairing to a purine at the site of modification. 3) We will evaluate the ability of modified siRNAs to engage in sequence-dependent and sequence-independent off-target effects in RNAi. Sequence-dependent effects will be assessed by analyzing modified siRNA duplexes containing immunostimulatory sequence motifs for their ability to stimulate immune responses in mice and in cultured murine immune cells including myeloid dendritic cells. Sequence-independent effects will be evaluated by determining the consequence of base modifications on the binding of cellular duplex RNA-binding proteins
Keywords: 8-hydroxyguanosine; Acrolein; alkyl group; Alkylation; base; Base Pairing; Binding (Molecular Function); Cells; Chemicals; Collaborations; Dendritic Cells; design; Development; Digestion; Gene Expression; gene function; Gene Silencing; Guanine; Guanosine; Health Sciences; Human; human TLR7 protein; Immune; Immune response; Lesion; Life; Major Groove; Mediating; Messenger RNA; Microarray Analysis; Minor Groove; Modification; Molecular; Molecular Biology; Mus; Myelogenous; new technology; novel therapeutics; nuclease; nucleobase; Oligonucleotides; Pathology; Pattern; phosphoramidite; Positioning Attribute; professor; Protein Binding; Proteins; purine; Purines; Research Personnel; Ribonucleotides; RNA; RNA Interference; RNA Interference Pathway; RNA Sequences; RNA-Binding Proteins; Shapes; Site; Toll-like receptors; Universities; Utah
Project start date: 2007-04-01
Project end date: 2012-03-31
Budget start date: 1-APR-2010
Budget end date: 31-MAR-2012
PFA/PA: RFA-HL-05-019
5R01GM080784-04 (2010): $254605
5R01GM080784-03 (2009): $257367
5R01GM080784-02 (2008): $257548
1R01GM080784-01 (2007): $246564
THE ROLE OF THE NICOTINIC CHOLINERGIC PATHWAY IN RETINOPATHY OF PREMATURITY
A Peter
Stanford Universitycity: Stanford country: United States (us)
Grant 1R01EY020609-01A1 from National Eye Institute
Abstract: Retinopathy of prematurity (ROP), is a leading cause of vision impairment and blindness in children in the United States, due to pathological retinal neovascularization. We have discovered a novel angiogenic pathway that is involved in pathological neovascularization. This pathway is mediated by an endothelial nicotinic acetylcholine receptor (nAChR). The endothelial nAChR is a ligand-gated cationic channel that is activated by the endogenous signaling molecule, acetylcholine (ACh). Activation of this receptor induces endothelial cell mitogenesis, migration and tube formation and promotes angiogenesis. The pathway is upregulated by hypoxia, and by other angiogenic factors such as the vascular endothelial growth factor (VEGF). Accordingly, we propose the following Specific Aims to develop a novel therapy for ROP 1. Characterize the endothelial nicotinic cholinergic pathway in the developing retina, and determine its role in normal vascularization. We hypothesize that normal development of the retina will not be adversely affected by pharmacological antagonism of the EC nAChRs. This hypothesis is based in part on the normal phenotype of the a7-nAChR deficient mouse. We will begin by determining, during normal development, the level of expression and localization of key elements of the nAChR pathway including the high affinity choline transporter, choline acetyltransferase, and the nAChR subunits. We will study EC from normal retinal vessels using laser capture microdissection and real time RT-PCR, in situ hybridization and immunohistochemistry. We will carefully assess vascular and neuronal development in the retina of the a7-nAChR deficient mouse. Finally, we will determine if pharmacological antagonism of nAChRs in the eye (comparing non-selective versus a7-nAChR selective antagonists) will adversely effect normal neuronal or vascular development. 2. Determine if excessive activation of this pathway contributes to retinal neovascularization in a murine model of ROP, using pharmacological and genetic knockdown of EC nAChRs. Using the methods described above, we will determine if retinal neovascularization is associated with increased retinal expression of any components of the nAChR pathway. We will determine if administration of the non-selective (mecamylamine) or a7-preferential (methyllycaconitine) nAChR antagonists suppress retinal neovascularization. The effect of nAChR antagonists on retinal neuronal function will be assessed by ERGs. ROP will be induced in a7- nAChR knockout mice and littermate controls to determine if signaling through a7- nAChRs contributes to retinal neovascularization. We will perform biochemical studies to assess the relationship between plasma and retinal levels of ACh, and correlate these levels to changes in retinal levels of vascular endothelial growth factor (VEGF), retinal vascularity and permeability. Abnormal blood vessel formation is a risk factor in retinopathy of prematurity. Retinopathy of prematurity (ROP) is a significant cause of vision impairment and blindness in more than 50% of premature infants as a result of abnormal blood vessel formation in the retina. The possible risk factors for ROP are the oxygenation of these infants after birth and the accumulation of growth factors that are responsible for the formation of abnormal blood vessels. In this study, we intend to understand the role of a particular receptor in these abnormal vessels and develop a new therapy to prevent visual loss and blindness in preterm infants
Keywords: Acetylcholine; Affect; angiogenesis; Angiogenic Factor; Arterial Fatty Streak; base; Biochemical; Biological; Birth; Blindness; Blood Vessels; cancer cell; Child; Choline O-Acetyltransferase; choline transporter; cholinergic; Cholinergic Receptors; Choroid; Choroidal Neovascularization; Development; diabetic; Disease; Drug Formulations; Elements; Endothelial Cells; Exudative age-related macular degeneration; Eye; Genetic; Growth Factor; human subject; Human Volunteers; Hypoxia; Immunohistochemistry; Impairment; In Situ Hybridization; Infant; Inflammatory; insight; Ischemia; Knockout Mice; laser capture microdissection; Lead; Learning; Ligands; macular edema; Malignant neoplasm of lung; Mecamylamine; Mediating; Medicine; Methods; methyllycaconitine; migration; Modeling; Mus; Nature; neovascularization; neuron development; Neurons; Nicotinic Receptors; novel; novel strategies; novel therapeutic intervention; novel therapeutics; Pathogenesis; Pathologic Neovascularization; Pathway interactions; Patients; Permeability; Phase; phase 1 study; Phase II Clinical Trials; Phenotype; Plasma; Pregnancy; Premature Infant; prevent; receptor; Receptor Activation; Research; Retina; retina blood vessel structure; Retinal; Retinal Detachment; Retinal Diseases; Retinal Neovascularization; retinal neuron; Retinopathy of Prematurity; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Safety; Sclera; Signal Transduction; Signaling Molecule; Stimulation of Cell Proliferation; Time; Traction; Tube; Tumor Angiogenesis; tumor growth; United States; Vascular Endothelial Growth Factors; Vascularization; Vision
Relevance: Abnormal blood vessel formation is a risk factor in retinopathy of prematurity. Retinopathy of prematurity (ROP) is a significant cause of vision impairment and blindness in more than 50% of premature infants as a result of abnormal blood vessel formation in the retina. The possible risk factors for ROP are the oxygenation of these infants after birth and the accumulation of growth factors that are responsible for the formation of abnormal blood vessels. In this study, we intend to understand the role of a particular receptor in these abnormal vessels and develop a new therapy to prevent visual loss and blindness in preterm infants
Project start date: 2011-09-30
Project end date: 2015-08-31
Budget start date: 30-SEP-2011
Budget end date: 31-AUG-2012
1R01EY020609-01A1 (2011): $414079
HNF1 TRANSCRIPTIONAL CONTROL OF RENAL OXIDATIVE STRESS
A Peter, Professor
University Of Texas Hlth Sci Ctr Houstoncity: Houston country: United States (us)
Grant 5R01DK069632-05 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Renal injury associated with hypertension, diabetes and the metabolic syndrome is a disease outcome of enormous cost to health and economic resources that, in contrast to other adverse outcomes, is increasing in prevalence. The pathogenesis of renal injury and its progression to end stage renal disease (ESRD) involves the generation of renal oxidative stress and resulting tissue injury. Unfortunately, little is known about the origin of this oxidative stress. It is unclear to what extent increased oxidative free radical production versus reduced free-radical scavenging contribute to the shift in redox balance. Furthermore, since multiple genes and proteins are involved both in radical production and in defense against radical injury, a comprehensive picture of the pattern of changes in these mechanisms as hypertensive renal injury develops is lacking. Our recent work analyzing the progressive changes in renal gene expression in an animal model of heritable hypertension in association with susceptibility to oxidative renal injury has generated two important observations first, the emergence of renal injury is preceeded by a clear and coordinated down-regulation of many genes involved in reactive radical scavenging; second, this coordinated pattern of functional change appears to be regulated by a single transcription factor abundantly expressed in kidney hepatocyte nuclear factor 1, HNF1. In the present studies, we will extend our gene array and bioinformatics methods to develop direct evidence supporting this mechanism of renal injury in hypertension by targeting HNF1 expression in vitro and in vivo. We will investigate the role of renal immune cell infiltration in hypertensive renal injury in which activated immune cells may release cytokines that play a key role in HNF1 transcriptional coordination of gene expression to produce redox stress. We will investigate whether the enhancement of renal injury by increased salt intake is attributable to increased oxidative stress mediated by HNF1 transcriptional control. Finally, we will address the role of oxidative stress in heritable susceptibility to renal injury by contrasting its development in two related animal models of hypertension differing in their genetic susceptibility to renal injury
Keywords: Address; Amplifiers; Animal Model; Animal Models and Related Studies; balance; balance function; Bio-Informatics; Bioinformatics; biological signal transduction; Blood Pressure, High; Body Tissues; Cell Communication and Signaling; Cell Signaling; Cells; Common Rat Strains; congenital hypertension; cost; cytokine; Data; Development; diabetes; Diabetes Mellitus; Disease Outcome; Down-Regulation; Down-Regulation (Physiology); Downregulation; End stage renal failure; End-Stage Kidney Disease; Equilibrium; ESRD; Essential Hypertension; familial hypertension; Free Radical Scavenging; Free Radicals; Gene Expression; Gene Proteins; gene therapy; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; Generations; Genes; genetic etiology; genetic hypertension; Genetic Intervention; genetic mechanism of disease; Genetic Predisposition; Genetic Predisposition to Disease; Genetic Susceptibility; genetic therapy; genetic vulnerability; Goals; health economics; hepatic nuclear factor 1; hepatocyte nuclear factor 1; HNF-1 protein; hyperpiesia; hyperpiesis; Hypertension; hypertensive disease; idiopathic hypertension; Immune; In Vitro; in vivo; Infiltration; Inflammation; INFLM; Inherited Predisposition; Inherited Susceptibility; Injury; Intervention, Genetic; Intracellular Communication and Signaling; Kidney; Knowledge; Link; Mammals, Rats; Mediating; Metabolic syndrome; Methods; model organism; Modeling; Molecular Biology, Gene Therapy; nuclear protein LF-B1; Outcome; oxidation reduction reaction; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pattern; Play; Predisposition; Prevalence; primary hypertension; Production; Protein Gene Products; Rat; Rattus; Redox; Regulation; renal; Renal Disease, End-Stage; Research Resources; Resistance; resistant; Resources; Role; salt intake; Signal Transduction; Signal Transduction Systems; Signaling; social role; Stress; Susceptibility; Testing; Therapy, DNA; Tissues; transcription factor; transcription factor APF; transcription factor HNF1; transcription factor HP1; transcription factor LF-B1, liver specific; transcription factor LFB1; Transcription Regulation; Transcriptional Control; Transcriptional Regulation; Urinary System, Kidney; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Work
Project start date: 2005-08-01
Project end date: 2011-07-31
Budget start date: 1-AUG-2009
Budget end date: 31-JUL-2011
5R01DK069632-05 (2009): $279181
A Peter, Associate Professor
Case Western Reserve Universitycity: Cleveland country: United States (us)
Abstract: PROJECT SUMMARY (See instructions) The Molecular Diagnostics Core will support the three major research projects and interact directly with the Database and Biostatistics Core in the organization of an archive of biological material that will be collected during the course ofthe research projects. Core activities include the application of existing methods for identifying parasite and mosquito species and strains by conventional microscopy, current molecular diagnostic methods, and by newly emerging cell biology and DNA sequencing technology. The Specific Aims are to 1 Create an ICEMR Archive of human blood samples and mosquitoes for characterizing malaria species and strains, and for evaluating immunological parameters of infection by Plasmodium species and clinical malaria 2 Develop PCR-based assays to diagnose Plasmodium species Infections of human study participants and mosquitoes 3 Develop PCR-based assays to diagnose Infection by Plasmodium strains in human study participants and mosquitoes 4 In collaboration with the Transmission Project, develop PCR-based assays to perform mosquito speciation, process mosquitoes for blood meal source and monitor permethrin resistance 5 Develop microscopy- and PCR-based assays to diagnose Plasmodium gametocyte stages in human study participants 6 Evaluate and develop strategies based on advanced DNA sequencing strategies to analyze complexity of Plasmodium species infections and Anopheles mosquito diversity using polymorphisms distributed across the parasite and vector species genomes 7 Build capacity and transfer technology to partner institution laboratories in malaria endemic sites The Molecular Diagnostics Core will be directed by Prof. Zimmerman who has worked with PNGIMR (Mueller), the Swiss Tropical Institute (Felger) and UQ (Cooper and Beebe) on malaria epidemiology and mosquito ecology for >10 years. He will be assisted by I Felger, now at STI and previously an employee of PNGIMR. Capacity building and training in the malaria endemic site will be assured by the continuing high commitment of this team to expanding cost effective technologies to the region covered by the ICEMR
Keywords: Address; Advanced Development; Alleles; American; Anopheles Genus; Anticoagulants; Antigens; Archives; artemisinine; Artemisinins; Asia; assay development; base; Biocompatible Materials; Biological; Biological Assay; Biostatistics Core; Blood; Blood specimen; Cataloging; Catalogs; Cellular biology; Clinical; Collaborations; Combined Modality Therapy; Complex; computerized data processing; cost; cost effective; Cryopreservation; Culicidae; Data; Data Analyses; Databases; Dengue Virus; Detection; Development; Diagnosis; Diagnostic; Diagnostic Specificity; disorder control; DNA; DNA Sequence; Ecology; Edetic Acid; Employee; Ensure; Entomology; Enzyme-Linked Immunosorbent Assay; Epidemiology; epidemiology study; Erythrocytes; Evaluation; experience; Family member; FarGo; Filaria bancrofti; Genetic; Genetic Markers; Genetic Polymorphism; Genome; genome sequencing; Genotype; Health; Human; Human Parvovirus B19; human study; Hygiene; Immunology; improved; Individual; Infection; Insecticides; Institutes; Institution; Instruction; Intervention; Journals; Laboratories; Lead; Length; Leptospira interrogans; Leptospirosis; Leukocytes; Ligase; Location; Malaria; Measures; Medical Research; member; Methodology; Methods; Microsatellite Repeats; Microscopy; Microspheres; Molecular; Molecular Diagnostic Techniques; Monitor; nucleic acid purification; Nucleic Acids; Papua New Guinea; Parasites; Participant; pathogen; Pathogenesis; Performance; Permethrin; Pharmaceutical Preparations; Plasma; Plasmodium; Plasmodium falciparum; Polymorphic Microsatellite Marker; Population; Population Genetics; Population Sizes; Preparation; Procedures; Process; programs; public health medicine (field); Publishing; Queensland; Reaction; Research; Research Design; Research Personnel; Research Project Grants; Research Proposals; research study; Resistance; Resources; RNA; Role; sample collection; Sampling; Schedule; Series; Serum; Siblings; Single Nucleotide Polymorphism; Site; Solomon Islands; Source; Speed (motion); Sporozoites; Staging; Structure; Students; Techniques; Technology; Technology Transfer; Thick; Training; transmission process; Tropical Medicine; Tube; Universities; Update; Vanuatu; vector; vector mosquito; Vector-transmitted infectious disease; Whole Blood; Work
Relevance: Cost effective and high throughput methodologies ranging from microscopy, ELISA formats and most recently nucleic acid (DNA and RNA) interrogation techniques will facilitate malaria research and the monitoring and evaluation of public health interventions aimed at malaria control and elimination. These resources are rightfully based in malaria endemic settings where such large scale public health programs are expanding
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5U19AI089686-02_6402 (2011): $142622
Sponsored Links Excellgen http://Excellgen.com
THE ROLE OF KV1.3 IN EFFECTOR T CELLS
A Peter, Associate Professor & Director Ms Center
Johns Hopkins Universitycity: Baltimore country: United States (us)
Grant 5R01NS041435-11 from National Institute Of Neurological Disorders And Stroke
Abstract: Potassium (K+) channels expressed in immune cells have gained attention recently as promising targets of immunotherapy for multiple sclerosis (MS). We have previously shown that naove and central memory T cells (TCM) predominantly use the calcium-dependent potassium channel KCa3.1 during acute activation, whereas effector memory T cells (TEM), which are likely to be the pathogenic population in MS, utilize the voltage-gated potassium channel Kv1.3. Further, only TEM were inhibited by Kv1.3- specific pharmacological blockade, as naove T cells and TCM bypassed this inhibition via up regulation KCa3.1, indicating the potential for selectivity of this approach. Myelin reactive T cells from MS patients have higher levels of Kv1.3 than either control antigen specific T cells or myelin reactive T cells from healthy volunteers. We have further demonstrated that the inflammatory infiltrate in MS brain tissue consists almost entirely of TEM and that these cells highly express Kv1.3. To better define the specific role of Kv1.3, we have generated a lentivirus construct that expresses a dominant negative (DN) form of Kv1.3 and have recently shown that transduction of CD4+ Tcell subsets with the Kv1.3DN both inhibits differentiation from TCM into TEM and mediates reversion of TEM into TCM. To identify target genes that contribute to these effects, we analyzed gene expression patterns by microarray, which showed significant differences in membrane microdomain, cell cycle, and differentiation genes as a result of Kv1.3 inhibition. The underlying hypothesis of this grant renewal is that Kv1.3 plays a major role in TEM cell derivation and biological function, and that selective blockade of this channel can reversibly inhibit the pathogenic consequences of these cells without compromising the TCM pool that is required for recall immune responses to pathogens. From our preliminary data, we are hypothesizing that Kv1.3 blockade disrupts T cell cycle and differentiation and will test this hypothesis in aim 1. The ultimate goal of this approach is to develop a new therapy for MS, and several pharmaceutical companies are currently generating Kv1.3 peptidyl blockers. Gaining a greater understanding of the in vivo effects will also be necessary for clinical translation. Towards this end, we will examine the effects of Kv1.3 inhibition on T cell infiltration, microglial activation, demyelination, and axon pathology in rat EAE models (Aim 2). The results of these experiments will allow us to better understand the therapeutic potential and safety of Kv1.3 blockade, and may have important implications for the design of upcoming human clinical trials of Kv1.3 blockers. Further, understanding basic mechanisms of T cell function will enhance our knowledge of how the immune system causes disease and allow us to develop novel strategies for correcting abnormal immune responses in diseases like MS. The relevance of this research is in its ultimate goal to develop a new therapy for Multiple Sclerosis. The results of these experiments will allow us to better understand the therapeutic potential and safety of Kv1.3 blockade, and may have important implications for the design of upcoming human clinical trials of Kv1.3 blockers. Further, understanding basic mechanisms of T cell function will enhance our knowledge of how the immune system causes disease and allow us to develop novel strategies for correcting abnormal immune responses in diseases like MS
Keywords: Acute; Affect; Aftercare; anergy; Antigens; Attention; Autoantigens; Autoimmune Diseases; Axon; base; Biological Process; brain tissue; Bypass; Calcium; cdc Genes; Cell Cycle; Cell Differentiation process; Cell physiology; Cells; Clinical; Clinical Trials; Cyclin B; cyclin T1; Cyclins; Data; Demyelinations; Derivation procedure; design; Development; Disease; Dominant-Negative Mutation; Experimental Autoimmune Encephalomyelitis; Future; Gene Expression; Gene Targeting; Genes; Goals; Grant; Health; healthy volunteer; Human; Immune; Immune response; Immune system; Immunologics; Immunotherapy; improved; in vivo; Infiltration; Inflammatory Infiltrate; inhibitor/antagonist; Knowledge; MADH3 gene; Mediating; Membrane Microdomains; Modeling; mouse model; Multiple Sclerosis; Myelin; Neurons; novel strategies; pathogen; Pathology; Patients; Pattern; Pharmacologic Substance; Phenotype; Play; Population; Potassium; Potassium Channel; Rattus; Relapse; Research; research study; Role; Safety; Signal Pathway; Signal Transduction; Site; Subfamily lentivirinae; T cell anergy; T cell differentiation; T cell regulation; T memory cell; T-Lymphocyte; terminally differentiated effector memory (TEM) T cells; Testing; Therapeutic; Therapeutic Effect; Translations; Up-Regulation (Physiology); Voltage-Gated Potassium Channel
Project start date: 2000-07-01
Project end date: 2013-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01NS041435-11 (2011): $347816
A Peter, Professor
University Of Texas Hlth Sci Ctr Houstoncity: Houston country: United States (us)
Grant 5R01DK081866-02 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Over 400,000 Americans have end-stage renal disease (ESRD) requiring dialysis or kidney transplant for survival. ESRD in the US population doubled in the last decade and this increase is driven by diabetes and hypertension. ESRD is associated with very high rates of mortality, most frequently from cardiovascular disease (CVD), and the heightened risk of CVD in individuals with chronic renal injury means that they are much more likely to die of CVD than to progress to ESRD. There is great variation in risk for ESRD among individuals who have hypertension and/or diabetes. The major determinant of this variation in risk is genetic susceptibility that serves to enhance the capacity of hypertension and diabetes to generate renal injury. The proposed studies focus on an animal model of renal injury with concurrent hypertension, insulin resistance and dyslipidemia, the spontaneously hypertensive rat (SHR). This model recapitulates the role of genetic susceptibility to renal injury in hypertensive and diabetic patients the SHR-A3 line acquires hypertensive renal injury, while other hypertensive SHR lines resist it. These contrasting SHR lines offer a valuable means to identify the mechanism of and the genes contributing to susceptibility to renal injury. The proposed studies are made possible by our recent progress in defining a set of high density, single nucleotide polymorphism (SNP) markers in our injury-prone (SHR-A3) and resistant (SHRB2) lines that allow high resolution genetic mapping of loci controlling susceptibility to renal injury. We propose here to use these markers to map an intercross of these parental lines that will identify injury susceptibility loci. The conclusions of our mapping study will be tested and verified by breeding reciprocal congenic strains that fix injury resistance and susceptibility alleles in the injury-prone SHR-A3 and the injury-resistant SHR-B2 lines. Finally, we have uncovered the role of renal redox stress in the generation of renal injury in SHR-A3 and identified a transcriptional program that leads to this redox stress. This provides an opportunity to refine our genetic mapping studies down to the level of specific genes within the mapped loci. Genes that are functionally correlated to the transcriptional pathway of renal redox stress that we have elucidated in SHR-A3 will be targeted for selective resequencing to identify specific gene variants that drive the renal injury pathway. PUBLIC HEALTH RELEVANCE Kidney injury caused by diabetes and high blood pressure requires that more than 400,000 Americans be treated by kidney dialysis in order to survive. Heredity plays a major role in risk of kidney injury. Among diabetic and high blood pressure patients, the largest risk of progressive kidney disease is the occurrence of this disease in a relative. In the proposed studies we will use a rat model of this syndrome to genetically map chromosomal regions harboring genes that create risk of kidney injury. By uncovering the genes that cause this injury in rats and how this injury is created by these genes we will open up valuable new opportunities to understand the disease in people and to envision and test new treatments
Keywords: Alleles; American; Animal Model; Breeding; Cardiovascular Diseases; cardiovascular disorder risk; Chromosome Mapping; Chronic; congenic; Congenic Strain; Control Locus; density; Diabetes Mellitus; diabetic; diabetic patient; Dialysis procedure; Disease; DNA Resequencing; Dyslipidemias; End stage renal failure; Generations; Genes; Genetic Predisposition to Disease; genome-wide; Heredity; Hypertension; Inbred SHR Rats; Individual; Injury; Insulin Resistance; Kidney; Kidney Diseases; Kidney Transplantation; Maps; Modeling; Mortality Vital Statistics; Oxidation-Reduction; Pathway interactions; Patients; Play; Population; Predisposition; programs; public health relevance; Rattus; Relative (related person); Renal dialysis; Resistance; Resolution; Risk; Role; Single Nucleotide Polymorphism; Speed (motion); Stress; Syndrome; Testing; Variant; Variation (Genetics)
Project start date: 2009-09-25
Project end date: 2012-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01DK081866-02 (2010): $349971
RESURFACING DAMAGED ARTICULAR CARTILAGE TO REGAIN FUNCTIONAL PROPERTIES
A Peter
Hospital For Special Surgerycity: New York country: United States (us)
Grant 5R21AR059203-02 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: Osteoarthritis (OA) is a disease which causes loss of joint function due to damage and deterioration of the articular cartilage. Damage usually begins at the articular surface from long-term wear or trauma, and is characterized by irreversible rupture (fissure) of the collagen fibrillar network within the superficial zone (SZ). SZ damage increases surface porosity, permeability and interstitial fluid exudation, resulting in loss of the cartilage´s ability to resist joint compressive loading and increased proteoglycan (PG) loss from the middle and deep zones. Two of the primary mechanisms causing damage to the collagen at the surface are from injurious or excessive mechanical loads (EML) and enzyme cleavage by matrix metalloproteinases (MMPs). Currently there are no therapeutic treatments to repair the surface damage and regain the cartilage´s functional properties to prevent progression to OA. The goal of this R21 application is to develop novel non-cell based methods to modify the articulating surface of articular cartilage to regain its ability to resistant damage by EML and MMPs and inhibit progression of matrix degradation. We propose to use new concepts of molecular engineering to modify and repair the articular surface damage, specifically the degraded collagen in the SZ, by repairing (cross-linking) the damaged collagen and replacing (attaching/embedding) the lost macromolecules (SZ proteins) within the SZ to restore extracellular matrix (ECM)function. Our molecularengineering approach is fundamentally different from cartilage engineered scaffolds that rely on cell-based regeneration into tissue having equivalent functional properties. Here we propose to repair damaged cartilage at the molecular level to make it resistant to mechanical and catabolic degradation, and more important, to restore and enhance the tissue´s functional properties. Our molecular engineering approach is a "model system" that has the potential for a much broader application for the repair of many types of damaged and diseased musculoskeletal tissues, such as in wound healing of skin, ligaments, tendons, meniscus, and neural tissues. Our overall(long-term) hypothesis is thatonce the functionalproperties of these tissues are reestablished, they will respond metabolically to remodel the extracellular matrix (ECM) to a native state. This proposal represents the first attempt (high risk, high impact) to develop a "non-cellular based, molecular engineering" approach for the repair of damaged tissues to improve their function and survival; that is, improvement in mechanical function and resistance to biologicaldegradation (catabolism). Successfulapplication of this approach will have significant impact on the potential treatment modalities for tissue repair. 1
Keywords: Aging; Anterior; Arthritis; articular cartilage; Athletic Injuries; base; Biochemical; Biocompatible; Biological; Biological Models; Biomechanics; Biopolymers; Cartilage; cartilage repair; Catabolism; Cell physiology; Cells; Chondrocytes; Collagen; crosslink; Degenerative polyarthritis; Deterioration; disability; Disease; Engineering; Enzymes; Experimental Designs; Extracellular Matrix; Extracellular Matrix Degradation; falls; Fibrillar Collagen; Goals; Health Benefit; high risk; improved; injured; Injury; Intercellular Fluid; irradiation; joint function; Joints; kinematics; Ligaments; macromolecule; Matrix Metalloproteinases; Measures; Mechanics; Meniscus structure of joint; Methods; Modality; Modification; Molecular; Musculoskeletal; Musculoskeletal System; Natural regeneration; novel; novel therapeutics; Obesity; Pathologic Processes; Patients; Permeability; Porosity; prevent; Procedures; Process; Property; Proteins; Proteoglycan; relating to nervous system; repaired; Research; Resistance; Risk Factors; Rupture; scaffold; Secondary to; Skin; Staging; Structure; Surface; Swelling; Technology; Tendon structure; Tensile Strength; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Trauma; Ultraviolet Rays; United States; vehicular accident; Water Movements; Wound Healing
Relevance: Osteoarthritis is the leading cause of disability in the United States, causing irreversible damage to the articular cartilage covering movable joints. Presently there are no known treatments to prevent the loss of the joint cartilage. Treatments to repair the cartilage damage and restore joint function at an early stage would have significant health benefits to the patient
Project start date: 2010-06-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-06-418
5R21AR059203-02 (2011): $253231
IMMUNOLOGY OF INFECTION WITH NEISSERIA GONORRHOEAE
A Peter, Professor Of Medicine
Univ Of Massachusetts Med Sch Worcestercity: Worcester country: United States (us)
Grant 5R37AI032725-18 from National Institute Of Allergy And Infectious Diseases
Abstract: Neisseria gonorrhoeae is one of the two major pathogens involved in the majority of cases of sexually transmitted genital infection. Complement forms an important aspect of the innate immune system that impacts upon gonococcal infection. Prior work in our laboratory has shown that sialylation of gonococcal lipooligosaccharide (LOS) results in complement resistance by binding the host complement regulatory molecule, factor H. The porin molecule also binds factor H. In the first Specific Aim, we will investigate the role of an alternatively-spliced version of factor H, called factor H-like molecule 1 (FHL-1)in binding to gonococci and in regulating complement. Some strains of N. gonorrhoeae process complement (i.e. convert complement component-3 [C3b] to the inactivated form [iC3b]) and bind FHL-1, but not factor H. Cofactor activity of FHL-1 will be assessed using serum containing only FHL-1, but not intact factor H. Because both factor H and FHL-1 bind to cells, we will examine the roles of these two molecules in facilitating gonococcal attachment to immortalized cervical and urethral epithelial cells, in the second Specific Aim, three questions that pertain to LOS sialylation will be addressed. First, the specificity of factor H binding to gonococcal lacto- N-neotetraose (LNT) sialic acid, but not to meningococcai LNT sialic acid, will be examined. Porin (Por) influences binding of fH to gonococcal sialic acid. We will perform allelic exchange of porin molecules between the two species to examine the effect of porin on the sialylated LOS interactions with factor H that differs at baseline in the two neisserial species. Second, we will examine the determinants of the functional specificity of the LOS sialyltransferase (IsO enzyme in meningococci and gonococci by performing allelic exchanges of the Ist genes between the two species. Third, we will also determine why the efficiency of LOS sialylation differs between serum-sensitive (high sialic acid uptake) and "stably" serum-resistant (low sialic acid uptake) gonococci. This will be performed by examining the uptake of 3H-labeled CMP-NANA by isogenic gonococci differing only in their Lst enzymes. The possibility that Por modifies Lst activity will also be examined by performing allelic exchanges of the Por genes between high and low sialic acid incorporators. In the third Specific Aim, we will detail the linkages (amide versus ester) between C4 and LOS, the effects of hexose extension of the LOS on binding of C4 to LOS, and the impact of the bond formed between C4 and LOS on bactericidal killing
Keywords: Address; Amides; Asialoglycoprotein Receptor; Bacteria; bactericide; base; Binding (Molecular Function); C3bi; Cells; Cervical; Chemicals; Clinical; cofactor; Complement; Complement 3; Complement 3b; Complement Factor H; Cytidine Monophosphate N-Acetylneuraminic Acid; Data; Disease; enhancing factor; Enzymes; Epithelial Cells; Esters; Exhibits; Galactose; Genes; genital infection; Genital system; gonococcal porin; Gonorrhea; Hexoses; Immune system; Immunology; Infection; Killings; Label; Laboratories; lacto-N-neotetraose; Length; Light; Link; lipooligosaccharide; Macrophage-1 Antigen; Mediating; mimicry; Neisseria; Neisseria gonorrhoeae; Neisseria meningitidis; pathogen; Pathogenesis; Pathway interactions; porin; Process; programs; receptor; Regulation; Relative (related person); Research Personnel; Resistance; Rice; RNA Splicing; Role; Serum; Sialic Acids; sialylation; Sialyltransferases; Side; Specificity; Structure; Surface; uptake; Urethra; Variant; Work
Project start date: 1993-01-01
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5R37AI032725-18 (2011): $627461
TRAINET: DIABETES TYPE 1 PREVENTION
A Peter
University Of Colorado Denvercity: Aurora country: United States (us)
Grant 5U01DK085509-03 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Long-term objective To find intervention therapies that can delay, prevent or reverse the development of type 1 diabetes (T1D). Specific Aims 1) BHT-3021 Proinsulin DNA vaccine treatment of recent onset type 1 diabetes subjects Research Design Preliminary data in animals has shown that using a similar proinsulin DNA vaccine can reverse diabetes in hyperglycemic mice. Pre-clinical studies in mice and non-human primates have found no toxicity for this therapy and have suggested a dosing scheme which could be effective in human subjects with T1D. An ongoing phase 1 study has confirmed the safety of this treatment and has suggested potential efficacy in type 1 diabetes subjects >3 months from diagnosis who still have C-peptide present. The current trial will test 2 doses, 1 and 3 mg, given weekly for 12 doses in a new onset patient population. It will use established measures to determine the effect on C-peptide, HbA1c, total insulin use and other safety parameters. Mechanistic studies to look at effects on insulin and other autoantibodies, T cells and other immune effects will be performed to better understand the potential mechanism of effect. 2) Renewal of TrialNet Center Research Design The Barbara Davis Center has been at the forefront of defining populations at risk for T1D and other autoimmune diseases and in recruiting patients for the TrialNet Natural History study as well as other TrialNet studies. The BDC TrialNet Center has helped to develop two of the first protocols, TN02 (MMF and DZB in new onset T1D), and TN06 (Nutritional Intervention to Prevent [NIP] Diabetes). Our proposal for renewal outlines our past efforts, current approaches and future goals to not only maintain our current level of productivity, but to increase productivity over the next funding cycle. The purpose of this research is to investigate methods to prevent diabetes and/or to prolong insulin production in people who have been recently diagnosed with type 1 diabetes
Keywords: Animals; Autoantibodies; Autoimmune Diseases; C-Peptide; Data; Development; Diabetes Mellitus; Diagnosis; Dietary Intervention; DNA Vaccines; Dose; Double-Blind Method; Funding; Future; Glycosylated hemoglobin A; Goals; human subject; Hyperglycemic Mice; Immune; Insulin; insulin dependent diabetes mellitus onset; Insulin-Dependent Diabetes Mellitus; Measures; Methods; Mus; Natural History; nonhuman primate; patient population; Patients; phase 1 study; phase 2 study; Placebo Control; Populations at Risk; preclinical study; prevent; Prevention; Principal Investigator; Production; Productivity; programs; Proinsulin; Protocols documentation; public health relevance; Randomized; Recruitment Activity; Research; Research Design; Safety; Scheme; T-Lymphocyte; Testing; Therapeutic Intervention; Toxic effect
Project start date: 2009-09-30
Project end date: 2014-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: RFA-DK-08-011
5U01DK085509-03 (2011): $612812
KETONE BODY METABOLISM AND INTEGRATED METABOLIC HOMEOSTASIS
A Peter, Assistant Professor Of Medicine
Washington Universitycity: Saint Louis country: United States (us)
Grant 1R01DK091538-01A1 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Ketone bodies are an avidly oxidized cellular fuel source, produced in abundance during the neonatal period, starvation, decompensated diabetes, and by adherence to low-carbohydrate (e.g., Atkins) diets. Ketones are known to be metabolically important for two reasons first, their accumulation in blood can promote ketoacidosis - elicited by mismatch between rates of ketogenesis and ketone body oxidation. Second, depending on physiological state, ketones supply up to 40% of the carbon backbones that yield high-energy phosphates. While the adverse consequences of ketoacidosis are well-appreciated, experimental models to date have not revealed whether loss of ketone oxidation can be energetically tolerated. Preliminary studies from this laboratory show that germline Oxct1-/- mice, which lack the enzyme critical for ketone body utilization, succinyl-CoA3-oxo-transferase (SCOT), are not viable after the second postnatal day. The proposed study will test the central hypothesis that ketone bodies serve an obligate energetic role in select physiological states, in that deficiencies of ketone body oxidation create metabolic abnormalities in the neonatal period and during nutrient deprivation in the adult. To specifically examine the energetic effects of ketolytic deficiency, independent of ketoacidosis, this laboratory also recently developed tissue-specific loss-of-SCOT-function mouse models that will be used within the following Specific Aims. The first aim will demonstrate the tissue- specific energetic requirement for ketone metabolism in the neonatal period. Using skeletal myocyte-, cardiac myocyte-, and neuron-specific Oxct1-/- mice, these experiments are expected to reveal the tissue(s) most dependent on ketones during the neonatal period. Next, using adult mice with loss-of-SCOT-function in skeletal muscle, collectively the largest ketone user and a key determinant of integrated metabolic homeostasis, the second aim will determine the role of ketone body metabolism in whole-body and skeletal muscle metabolism in the fed state and during prolonged nutrient deprivation. The third aim will use adult mice with loss-of-SCOT-function in heart to explore the role of ketone body metabolism in this high energy-requiring organ in the fed state and in the setting of nutrient deprivation. Because nutrient deprivation decreases glucose availability, elimination of ketone body oxidation is expected to elicit metabolic abnormalities, promote hypoglycemia, and when eliminated in cardiac muscle, contribute to the development of cardiomyopathy. Taken together, these studies will provide fundamental insight into the energetic roles of ketone body metabolism in a mammalian system, and therefore could ultimately influence (i) human newborn screening regimens, which currently do not test discrete disorders of ketone metabolism, (ii) the development of new risk- stratifying biomarkers for adult metabolic disease, and (iii) the development of individualized metabogenomics- guided nutritional regimens. Ketone body metabolism is an evolutionarily conserved metabolic pathway that is an important contributor to metabolic homeostasis in the neonatal period and in post-absorptive states. Despite numerous experiments that have quantified ketone body utilization, contexts in which ketone bodies are energetically essential have not been described. Novel mouse mutant strains, engineered with tissue-specific deficiencies of ketone body metabolism, are expected to reveal ketoacidosis-independent energetic requirements for ketone metabolism in the neonatal period and during nutrient deprivation in the adult. Therefore, the scope of prospective implications of these studies extends from the prevention of Sudden Infant Death Syndrome to avoiding and treating complications of adult metabolic disease
Keywords: Adherence (attribute); Adult; adverse outcome; Atkins Diet; biomarker; Birth; Blood; Body Weight decreased; Brain; Carbohydrates; Carbon; Cardiac Myocytes; Cardiomyopathies; Citric Acid Cycle; clinical care; deprivation; Development; Diabetes Mellitus; Disease; Disease Management; Engineering; Enzymes; Epilepsy; Exhibits; Experimental Models; fatty acid oxidation; Fatty Acids; feeding; flexibility; Glucose; glucose metabolism; glucose transport; Heart; heart metabolism; Hepatic; Homeostasis; Hour; Human; Hypoglycemia; Impairment; in vivo; Individual; Infant; inorganic phosphate; insight; ketogenesis; Ketone Bodies; Ketones; Label; Laboratories; Laboratory Study; Liver; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Modeling; mouse model; Mus; Muscle Fibers; muscle metabolism; Mutant Strains Mice; Myocardial; Myocardium; Neonatal; Neonatal Screening; Neurons; novel; Nutrient; Nutritional; Organ; oxidation; Physiological; postnatal; Prevention; prospective; recombinase; Regimen; Relative (related person); research study; response; Risk; Role; Skeletal muscle structure; Source; Starvation; succinyl-coenzyme A; Sudden infant death syndrome; System; Testing; Tissues; Transferase; Transgenic Organisms; Vertebral column
Relevance: Ketone body metabolism is an evolutionarily conserved metabolic pathway that is an important contributor to metabolic homeostasis in the neonatal period and in post-absorptive states. Despite numerous experiments that have quantified ketone body utilization, contexts in which ketone bodies are energetically essential have not been described. Novel mouse mutant strains, engineered with tissue-specific deficiencies of ketone body metabolism, are expected to reveal ketoacidosis-independent energetic requirements for ketone metabolism in the neonatal period and during nutrient deprivation in the adult. Therefore, the scope of prospective implications of these studies extends from the prevention of Sudden Infant Death Syndrome to avoiding and treating complications of adult metabolic disease
Project start date: 2011-08-05
Project end date: 2016-05-31
Budget start date: 5-AUG-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-10-067
1R01DK091538-01A1 (2011): $380000
IN VIVO CHARACTERIZATION OF THE PATHOGENESIS OF MODIFIED RHCMV VECTORS (PATHOGENE
A Peter, Professor
Oregon Health And Science Universitycity: Portland country: United States (us)
Abstract: instmctions) A critical issue related to the translation of RhCMV as a vaccine vector for foreign antigens to human trials is the demonstration that the RhCMV vectors are sufficiently attenuated so as to exhibit reduced parameters of viral growth. This is particularly true for those monkeys without a fully functional immune system under clinical scenarios that recapitulate the human condition. In addition to asymptomatic infections in immune competent hosts, modified RhCMV vaccine vectors should induce less disease in monkeys that are immune deficient by coinfection with SIV or iatrogenically immunosuppressed, and fetuses with intrauterine RhCMV infection. This Core will evaluate vectors constructed as part of the parent proposal for replication and safety in two monkey models of immune compromise immune immaturity associated with fetal development, and transplant-associated immune suppression. The mission of Core C is to define the replication and pathogenic potentials of RhCMV/SIV vectors in fetal and adult monkeys. Fetal Pathogenesis Model HCMV has long been recognized as an infectious threat to the fetus, especially in the context of primary HCMV infection of the mother. Our work with the rhesus model of intrauterine HCMV pathogenesis has shown that fetal macaques exposed to RhCMV exhibit nearly identical developmental abnormalities as children congenitally infected with HCMV. The fetus is acutely permissive to replicating RhCMV and presents a sensitive in vivo evaluation ofthe replication and pathogenic potentials ofthe modified vectors. Adult Pathogenesis Model HCMV is also the primary infectious cause of morbidity and mortality in solid organ and bone marrow transplant recipients. Similar to transplant-associated reactivation of HCMV, simian CMV disease has been observed in immunosuppressed nonhuman primates (NHP) receiving either allografts or xenografts. We have shown that reactivation of simian CMV following iatrogenic immunosuppression leads to severe pneumonitis and pulmonary vasculopathy. As another measure of attenuation of the RhCMV constructs of Projects 1 and 2, the pathogenic potential of vectors that are the lead candidates for human efficacy trials will be investigated in the context of depressed immune function in adult animals. RELEVANCE (See instructions) This Core will rigorously test the RhCMV vectors for residual levels of replication and pathogenesis. The results ofthis Core will be essential for moving candidate vectors forward to human clinical trials by critically evaluating the growth potential ofthe modified RhCMV vectors in vivo. Our productive history with the rhesus model of HCMV demonstrates our ability to meet the time schedule of the Project. PROJECT/PERFORIVIANCE SITE(S) (if additional space is needed, use Project/Perfonnance Site Fomiat Page) Project/Performance
Keywords: Adult; AIDS Vaccines; Allografting; Animal Virology; Animals; Antigens; Attenuated; attenuation; Auditory; Bone Marrow Transplantation; Cells; Cessation of life; Child; Clinical; Clinical Trials; Competence; Complex; congenital infection; Cytomegalovirus; Depressed mood; Development; Disease; efficacy trial; Evaluation; Exhibits; fetal; Fetal development of the mammalian embryo or fetus; Fetus; Growth; high risk; Histopathology; Human; Immune; immune function; Immune system; Immunohistochemistry; Immunology; immunosuppressed; in vivo; Infection; Instruction; Intravenous; Kinetics; Lead; Lung; Macaca; Macaca mulatta; mature animal; Measures; meetings; Mission; Modeling; Monkeys; Morbidity - disease rate; Mortality Vital Statistics; Mothers; Natural immunosuppression; Neuraxis; Neurologic; nonhuman primate; Organ; Outcome; Parents; Pathogenesis; Pathogenicity; Pathology; Patients; Performance; Pneumonia; Predisposition; prophylactic; Recording of previous events; relating to nervous system; Residual state; Risk; Safety; Saliva; Schedule; Sensorineural Hearing Loss; Sensory; Site; SIV; Solid; T memory cell; Techniques; Testing; Time; tissue tropism; Tissues; Translations; Transplant Recipients; Transplantation; Tropism; Urine; vaccine evaluation; Vaccines; Validity of Results; Variant; Vascular Diseases; vector; vector vaccine; Viral; Viremia; Work; Xenograft procedure
Project start date: 2011-07-15
Project end date: 2016-06-30
Budget start date: 15-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PAR-09-134
1P01AI094417-01_7721 (2011): $386065
TRANSCRIPTIONAL CONTROL BY THE GLOBAL REGULATOR SPX
A Peter, Professor
Oregon Health And Science Universitycity: Portland country: United States (us)
Grant 5R01GM045898-19 from National Institute Of General Medical Sciences
Abstract: In pathogenic bacteria, complex systems of control have evolved that activate defenses against the various toxic agents used by immune cells to combat infection. These systems regulate important virulence determinants, which are targets of drugs designed to alleviate infectious disease. The low GC Gram-positive bacteria have a unique system of transcriptional control, mediated by the protein Spx, that functions in the response to toxic oxidants, including those produced by phagocytic immune cells. Spx is a transcriptional regulator that we discovered in the spore-forming bacterium, Bacillus subtilis, but is also found in Staphylococcus aureus, Streptococcus pneumoniae, Listeria monocytogenes, and Bacillus anthracis. Spx has been shown to control the expression of virulence-associated activities in S. aureus, and is produced to high levels in Listeria monocytogenes and B. anthracis during host cell invasion. Spx defines a family of regulators that structurally resemble the enzyme arsenate reductase. It bears an N-terminal CXXC redox disulfide center that regulates its activity. Its mechanism of control is unique in that free Spx does not exhibit DNA-binding activity, but when bound to RNA polymerase (RNAP) in its oxidized disulfide form, it directs the enzyme to transcribe specific genes that function in oxidative stress defense. Spx concentration is reduced to low levels after recovery from stress by the protease ClpXP and the Spx-binding protein YjbH, which accelerates Spx proteolysis. The goal of the proposed research is to learn how B. subtilis Spx activates transcription initiation and how YjbH functions to mediate Spx proteolysis. Specific nucleotide sequence elements have been identified in the promoter regions of genes controlled by Spx. These sequences bind a complex of Spx and the C-terminal domain of RNAP subunit (CTD). The promoter DNA sequence and the structural requirements of CTD/Spx for promoter DNA binding will be determined. Furthermore, the dynamics of subunit positioning in RNAP holoenzyme within the Spx-activated transcription complex will be explored. Efficient proteolysis requires YjbH, a zinc-binding protein that interacts with Spx and accelerates ClpXP-catalyzed Spx proteolysis. Studies are proposed to investigate the oxidant-induced stabilization of Spx and redox control of YjbH activity. This study will focus on the Zn-binding site of the adaptor to test the model that oxidation of Zn-coordinating cysteine residues causes inactivation of YjbH and release of Spx. Differential thiol labeling and mass spectrometry will be performed to investigate the extent and nature of thiol oxidation of Spx and YjbH in vivo. A small protein factor, YirB that interacts with YjbH, will be studied to determine if it is a member of a growing list of small proteins that prevent protease-catalyzed degradation by inhibiting protease adaptor proteins. Complex systems of control have evolved in disease-causing bacteria to mobilize defenses that counter the toxic oxidizing agents produced by phagocytic immune cells. The regulatory protein Spx controls important components of the bacterial response to oxidative attack, and the study of its mechanism of action will uncover targets for neutralizing infectious microorganisms
Keywords: Adaptor Signaling Protein; Affect; Affinity; Ala-Trp-Arg-His-Pro-Gln-Phe-Gly-Gly; arsenate reductase; ATP-Dependent Proteases; Bacillus anthracis; Bacillus subtilis; Bacteria; Base Sequence; Binding (Molecular Function); Binding Proteins; Binding Sites; Biological Assay; C-terminal; cell envelope; Cells; Chimeric Proteins; cis acting element; Co-Immunoprecipitations; Code; combat; Communicable Diseases; Complex; Cysteine; Defect; Disease; Disulfides; DNA; DNA Binding; DNA Sequence; DNA Shuffling; DNA-Directed RNA Polymerase; DNA-protein crosslink; DNase-I Footprinting; Doctor of Medicine; Drug Design; Electrophoretic Mobility Shift Assay; Elements; Energy Transfer; Enzymes; Exhibits; Family; FeBABE; Fluorescence; Fluorescence Anisotropy; Gel; gene function; Genes; genetic regulatory protein; Genetic Transcription; Goals; Gram-Positive Bacteria; Holoenzymes; Immune; Immunoprecipitation; In Vitro; in vitro Assay; in vivo; Infection; Label; LacZ Genes; Learning; Listeria monocytogenes; Mass Spectrum Analysis; Measures; Mediating; member; Methods; microorganism; Modeling; Molecular Conformation; mutant; Mutation; N-terminal; Nature; Orthologous Gene; Oxidants; oxidation; Oxidation-Reduction; Oxidative Stress; pathogen; pathogenic bacteria; Peptide Hydrolases; Peptides; Positioning Attribute; prevent; Process; Promoter Regions (Genetics); Promotor (Genetics); Protein Family; protein protein interaction; Proteins; Proteolysis; public health relevance; Reaction; Recovery; Reducing Agents; Regulation; Reproduction spores; Research; research study; Resistance; Resolution; response; Response Elements; Screening procedure; Specific qualifier value; Staphylococcus aureus; stoichiometry; Streptococcus pneumoniae; Stress; Structure; Sulfhydryl Compounds; Surface; System; Technology; Testing; thioredoxin reductase; transcription factor; Transcription Initiation; Transcriptional Activation; Transcriptional Regulation; Ursidae Family; Virulence; zinc-binding protein
Relevance: Narrative Complex systems of control have evolved in disease-causing bacteria to mobilize defenses that counter the toxic oxidizing agents produced by phagocytic immune cells. The regulatory protein Spx controls important components of the bacterial response to oxidative attack, and the study of its mechanism of action will uncover targets for neutralizing infectious microorganisms
Project start date: 1992-02-01
Project end date: 2014-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01GM045898-19 (2011): $379643
3R01GM045898-19S1 (2011): $55386
A NON-HUMAN PRIMATE MODEL FOR CYTOMEGALOVIRUS VACCINES
A Peter, Professor
University Of California Daviscity: Davis country: United States (us)
Grant 5R01AI049342-09 from National Institute Of Allergy And Infectious Diseases
Abstract: HCMV is remarkably successful as demonstrated by (i) its ubiquity within the human population, (ii) periodic shedding of infectious virus in the presence of host immune responses, and (iii)its ability to infect previously immune hosts. These facts are not surprising considering the evolutionary genealogy of HCMV and the other members of Herpesviridae. Since viruses are obligate intracellular pathogens, the herpesviruses must have evolved comlex mechanisms to maintain themselves in host populations in the face of innate and adaptive barriers to viral replication. HCMV encodes a highly choreographed strategy of attenuating host immune responses to overcome the stringent requirements imposed by the viral life cycle. For any HCMV vaccine to be effective, it must elicit a level of protective immunity that is greater than that generated following primary infection with wild-type virus by impeding the virus´ ability to manipulate host immune responses. We previously proposed that HCMV immunomodulatory proteins should be included as vaccine targets since these proteins mediate the establishment of persistence. Results during the funding period demonstrate that cmvlL-10 treatment induces changes in dendritic cells (DC) functions in vitro. Inoculation of macaques with an IL-10-deleted variant of rhesus CMV (RhCMV) results in marked changes in the innate and adaptive immune responses. The results support the interpretation that cmvll_-10acts as an anti- inflammatory cytokine that skews host immunity at the earliest stage of viral infection. The hypothesis is presented that HCMV stimulates immune responses that, while protecting against disease, are insufficient to prevent persistence or protect against reinfection due to the actions of cmvll_-10. The hypothesis will be tested in rhesus macaques through the following Aims. (1) Immunization and challenge of macaques by a cmvlL-10 DMA priming/protein boost strategy followed by wild-type RhCMV challenge. (2) Immunization of macaques with RhCMVAILIO followed by RhCMV challenge. (3) Double immunization strategy of cmvlL-10 DMA priming/protein boosting and inoculation with RhCMVAILIO,followed by RhCMV challenge. (4) Site- directed mutation of the cmvll_-10 gene and protein. It is reasonable to expect that a successful HCMV vaccine strategy has to the match the complexity of HCMV natural history. This application seeks to demonstrate that a vaccine directed against cmvlL-10 should be included as one of the components
Keywords: Anti-Inflammatories; Anti-inflammatory; Anti-Inflammatory Agents; Antigen Presentation; Antigenic Determinants; Antigens; Antiinflammatories; Antiinflammatory Agents; Antiviral Agents; Antiviral Drugs; Antivirals; ATGN; Attenuated; base; Binding; Binding (Molecular Function); Binding Determinants; biological signal transduction; Cell Communication and Signaling; Cell Function; Cell physiology; Cell Process; Cell Signaling; Cellular Function; Cellular Physiology; Cellular Process; CMV; CMV vaccine; Complex; CSIF; CSIF-10; cytokine; Cytokine formation-inhibiting factor (mouse clone F115 protein moiety reduced); Cytokine Synthesis Inhibitory Factor; Cytomegalic Inclusion Disease; Cytomegalovirus; cytomegalovirus group; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Dendritic Cells; Disease; disease/disorder; Disorder; Epitopes; Evolution; Face; facial; Frequencies (time pattern); Frequency; Funding; gene product; Gene Proteins; Genealogy; Geneologies; Genetic Alteration; Genetic Change; Genetic defect; Genetic Differentiation; Genetic Divergence; Genetic Drift; genome mutation; HCMV; herpes virus; Herpesviridae; Herpesviruses; host response; Human; human cytomegalovirus; Human, General; IL-10; IL-10 receptor; IL10; IL10A; Immune; immune clearance; immune modulation; Immune response; Immunity; Immunization; Immunocompetent; immunogen; immunologic reactivity control; Immunologic Stimulation; Immunological Stimulation; Immunomodulation; immunoregulation; immunoresponse; Immunostimulation; In Vitro; Inclusion Disease; Individual; Infection; Inflammatory; Inflammatory Response; Interleukin 10 Precursor; Interleukin-10; interleukin-10 receptor; Intracellular Communication and Signaling; Invertebrata; Invertebrates; Invertebrates, General; Investigators; life course; Life Cycle; Life Cycle Stages; lymph gland; Lymph node proper; lymph nodes; Macaca; Macaca mulatta; Macaque; Maintenance; Maintenances; Man (Taxonomy); Man, Modern; Mediating; member; Modeling; Molecular Interaction; Monkeys; Mutation; Natural History; non-human primate; nonhuman primate; pathogen; Population; prevent; preventing; Production; progenitor; programs; Programs (PT); Programs [Publication Type]; Protein Gene Products; Proteins; Research Personnel; Researchers; response; Reticuloendothelial System, Lymph Node; Rhesus; Rhesus Macaque; Rhesus Monkey; RNA Viruses; Salivary Gland Virus Disease; Salivary Gland Viruses; Sensitization, Immunologic; Sensitization, Immunological; Signal Transduction; Signal Transduction Systems; Signaling; Site; Staging; Subcellular Process; subcutaneous; Surface; T-Cells; T-Lymphocyte; Testing; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; trafficking; vaccination strategy; Vaccines; Variant; Variation; Veiled Cells; Viral; Viral Burden; Viral Diseases; viral infection; Viral Load; Viral Load result; Viral Pathogenesis; Viral Shedding; Viral Sheddings; Virus; Virus Diseases; virus infection; Virus Shedding; Virus Sheddings; Viruses, General
Project start date: 2001-04-01
Project end date: 2011-11-30
Budget start date: 1-DEC-2009
Budget end date: 30-NOV-2011
5R01AI049342-09 (2010): $400912
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