BREAST CANCER GWAS: FUNCTION AND ENVIRONMENTAL INTERACTIONS
A Michael
University Of Wisconsin Madisoncity: Madison country: United States (us)
Grant 5R01ES017400-04 from National Institute Of Environmental Health Sciences
Abstract: Susceptibility to common diseases such as breast cancer is complex. Minimally the etiology of susceptibility is centered on a large number of interacting genetic elements which individually and collectively interact with environmental components. In order to assign risks to individuals, in contrast to populations, it will be necessary to refine an individual´s inherent risk alleles and their interaction with each other and the individual´s environment. To accomplish the goals of individual risk estimation and its mitigation, disease-specific integrated genetic systems networks are needed. Work will focus on breast cancer genome-wide association studies (GWAS) SNPs in ~10% of the human genome that is homologous to the highly defined mammary susceptibility QTLs in the rat. High throughput gene expression measurements from at least 50 reduction mammoplasty human mammary epithelial cells (HMEC) samples from healthy women together with full genome SNP genotypes will be obtained. Expression quantitative trait loci (eQTL) will be identified and integrated with GWAS results for breast cancer risk. The integrated data sets will be used for three important purposes. First, they will be used to assign function to a group of tag SNP alleles from breast cancer GWAS. The second will be to establish network systems models that suggest potential causal relationships among SNPs and downstream phenotypes. The third application of these integrated data sets will be to prioritize suspected but not yet validated tag SNP risk alleles for further validation studies using Wisconsin breast cancer case-control DNA samples (n = ~7,000). Next, investigating the effects of environmental factors on gene expression in HMEC will further develop and functionally explore the groups/networks of transcripts identified above. Primary cultures of HMEC will be exposed to xenobiotics chosen using prior knowledge. The expression levels of genes of interest will be evaluated asking if such agents (toxic and preventive) can modulate the expression of important groups of transcripts associated with GWAS SNPs and if exposure significantly alters network structure. GWAS SNPs that are associated with gene expression changes caused by specific xenobiotics will be used to determine if stratification by these SNPs modifies relative risk for that environmental agent in the Wisconsin case-control population. Finally, in vivo validation studies using the congenic rat mammary carcinogenesis models initially used to focus human studies will be conducted. The goal of this project is to develop an integrated approach combining global genetic information together with environmental exposure to form a network model that begins to describe the etiology of breast cancer. Such a model, when complete, could allow us to move from the estimation of population risk for breast cancer to individual risk. This model will also provide functional information underlying genetic/environmental risk that could lead to strategies for risk reduction to this disease
Keywords: Alleles; Architecture; Biological Models; Breast; Breast Cancer Model; Breast Diseases; cancer genome; cancer risk; case control; Case-Control Studies; Chemicals; Collection; comparative; Complex; Computational algorithm; congenic; Data; Data Set; Databases; Development; Disease; disorder prevention; DNA; Environment; environmental agent; Environmental Exposure; Environmental Risk Factor; epidemiologic data; Epidemiology; Epithelial Cells; Etiology; Exposure to; Gene Expression; Genes; Genetic; genetic element; Genome; genome wide association study; Genotype; Goals; high risk; Homologous Gene; Human; Human Genome; in vivo; Individual; interest; Knowledge; Lead; malignant breast neoplasm; Mammary gland; Mammary Tumorigenesis; Measurement; Measures; Medicine; Modeling; network models; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Prevention strategy; Preventive; public health relevance; Quantitative Trait Loci; Rattus; Relative Risks; Review Literature; Risk; Risk Estimate; Risk Reduction; Sampling; Series; Single Nucleotide Polymorphism; Stratification; Structure; System; Testing; Time; Transcript; validation studies; Wisconsin; Woman; Work; Xenobiotics
Relevance: The goal of this project is to develop an integrated approach combining global genetic information together with environmental exposure to form a network model that begins to describe the etiology of breast cancer. Such a model, when complete, could allow us to move from the estimation of population risk for breast can- cer to individual risk. This model will also provide functional information underlying genetic/environmental risk that could lead to strategies for risk reduction to this disease
Project start date: 2008-12-11
Project end date: 2013-10-31
Budget start date: 1-NOV-2011
Budget end date: 31-OCT-2012
5R01ES017400-04 (2012): $368522
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to A Michael
PSYCHOLOGICAL AND BEHAVIORAL IMPACT OF CANCER SCREENING
A Michael, Professor Of Behavioral Science
University Of Kentuckycity: Lexington country: United States (us)
Grant 5K05CA096558-05 from National Cancer Institute
Abstract: While cancer screening can reduce mortality and morbidity, participation in cancer screening can have a negative psychological and behavioral impact, even when no malignancy is detected. Understanding and management of the potential negative impact of cancer screening is the focus of the research and mentoring activities for this award. The PI has spent over 20 years conducting research in behavioral oncology and mentoring pre- and postdoctoral trainees. His career has focused on the psychological, social, and behavioral dimensions of cancer detection, diagnosis, treatment, and recovery. This award will enable him to continue to develop his research and mentoring activities. The research builds on the Pl´s ongoing study (R01 CA94036) of psychological and behavioral outcomes of transvaginal (TVS) screening for ovarian cancer and the Pl´s recent study of psychological and behavioral outcomes of benign breast biopsy (BBB). Three synergistic studies are proposed (1) prospective, longitudinal study of psychological and behavioral outcomes of an abnormal TVS screening result; (2) development and evaluation of brief psychoeducational interventions for managing the negative psychological and behavioral impact of BBB; and (3) development of brief psychoeducational interventions for managing the negative impact of an abnormal TVS screening result. The mentoring plan builds on the Principal Investigator´s prior experience as PI for three pre-and postdoctoral research training grants. Mentoring will be provided for 4-6 trainees each year. All trainees participate in an existing research training program in behavioral oncology. The training program consists of core elements (1) coursework; (2) participation in behavioral oncology research; and (3) participation in national professional meetings. These core elements enable achievement of training objectives (1) knowledge of the behavioral oncology literature; (2) knowledge of the medical basis of cancer; (3) participation in all phases of research; (4) acquisition of skills critical to both quantitative and qualitative research; (5) familiarity with medical settings in which cancer detection, diagnosis, and treatment occurs; and (6) professional development. The overall goal of the training program is to prepare trainees for careers as independent investigators in behavioral oncology
Keywords: ing; Accounting; Acquaintances; Address; Adherence (attribute); Adjuvant Therapy; Adoption; Advocate; Affect; Affective; Age; Age-Years; Analysis of Variance; anticancer research; Anxiety; Appendix; Appointment; Area; Arts; Attention; Attitude; Authorship; Award; Back; base; Basic Science; Behavior; behavior measurement; Behavioral; Behavioral Medicine; Behavioral Model; Behavioral Sciences; Belief; Benign; Biopsy; biopsychosocial; Breast; Breast Self-Examination; Budgets; Cancer Control; Cancer Detection; cancer diagnosis; Cancer Etiology; cancer risk; cancer therapy; career; Caring; Categories; Cause of Death; Cessation of life; Characteristics; Chi-Square Tests; Class; Clinic; Clinic Visits; Clinical; Clinical Management; Clinical Trials Design; Code; Cognition; Cognitive; cohort; college; Colon, Rectum; Communication; Comparative Study; comparison group; Computer information processing; Condition; Consent; Consent Forms; Contraceptive Usage; Control Groups; Controlled Clinical Trials; coping; Coping Behavior; Coping Skills; cost; cost effectiveness; Costs and Benefits; Counseling; Coupled; cyclobutanecarbonylcarnitine; Data; data acquisition; Data Analyses; day; Demographic Aging; demographics; depressive symptoms; design; Detection; Development; Diagnosis; Diagnostic; Diffuse; Dimensions; Discipline; Discipline of Nursing; Discipline of obstetrics; Disease; Disease regression; Disorder by Site; Distant; Distress; disturbance in affect; Doctor of Philosophy; Early Diagnosis; Educational aspects; Educational Materials; Educational process of instructing; Educational Status; Effectiveness of Interventions; Electronics; Elements; Eligibility Determination; End Point; Enrollment; Ensure; Environment; Epidemiologic Studies; Equilibrium; Evaluation; Event; Exhibits; Expectancy; experience; Exposure to; Faculty; falls; Familiarity; Family; Family Cancer History; Family history of; Fatigue; Feedback; Feeling; Female; Financial cost; Fine needle aspiration biopsy; First Degree Relative; Focus Groups; follow-up; Follow-Up Studies; Foundations; Friends; Funding; Funding Agency; Future; Goals; Grant; Grant Review; Growth; Head; Health; Health behavior; health belief; Health Psychology; High-Risk Cancer; implementation research; Incidence; Income; indexing; Individual; Individual Differences; Informal Social Control; Informed Consent; instructor; interest; Internet; Intervention; Intervention Studies; Interview; Joints; Kentucky; Knowledge; Lead; Life; Lifetime Risk; Link; Literature; literature survey; Location; Logistic Regressions; Logistics; Longitudinal Studies; Lung; Mails; male; Malignant - descriptor; malignant breast neoplasm; Malignant neoplasm of ovary; Malignant Neoplasms; Mammography; Manuals; Manuscripts; Marketing; Mass Screening; Measures; Mediation; Medical; Medical center; Medical Records; Medicine; member; Mental Depression; Mentors; Methods; Metric; Minor; Modality; Modeling; Monitor; Moods; Morbidity - disease rate; Mortality Vital Statistics; Motivation; Multivariate Analysis; Names; National Research Service Awards; Nature; Neuro-Oncological Ventral Antigen 2; Non-Malignant; Notification; Numbers; Occupations; Odds Ratio; oncology; optimism; Oral; Oral Contraceptives; Outcome; Outcome Measure; Paper; parity; Participant; Patient Self-Report; Peer Review; Perception; Personal Satisfaction; Persons; Phase; Physiological; Play; Polishes (substance); Population; Population Research; Positioning Attribute; positive mood; posters; Postmenopause; pre-doctoral; Predisposition; Premenopause; Prevention; Principal Investigator; Probability; Procedures; Process; Professional Practice; Professional Role; programs; prospective; prospectuses; protective behavior; Protocols documentation; psychoeducational intervention; psychologic; Psychologist; Psychology; psychosocial; Publications; Purpose; Qualitative Research; Quality of life; Questionnaires; Race; Randomized; Randomized Controlled Clinical Trials; Range; Rate; Reaction; Reading; Recommendation; Recording of previous events; Records; Recovery; Recruitment Activity; Regression Analysis; Rehabilitation therapy; Relative (related person); Reporting; Request for Applications; Research; Research Activity; research and development; Research Design; Research Methodology; Research Personnel; Research Project Grants; research study; Research Training; Resolution; Resort; Resources; response; Review Literature; Risk; Risk Estimate; Risk Factors; Role; role model; Role playing therapy; Sample Size; Sampling; Sampling Studies; Scanning; Schedule; Schools; Score; Screening for cancer; Screening for Ovarian Cancer; Screening procedure; Screening Result; Second Degree Relative; Secure; Senior Scientist Award; Severities; Shapes; Shipping; Ships; Side; size; skill acquisition; skills; social; social cognitive theory; Social Environment; Social Sciences; Social support; Societies; Solid; Source; Staging; Standards of Weights and Measures; Strategic Planning; Stress; stressor; Structure; Students; Study Section; success; Suggestion; Sum; Supervision; Support of Research; Surgeon; symposium; Symptoms; System; Tape Recording; Target Populations; Techniques; Telephone; Telephone Interviews; Test Result; Testing; theories; therapy development; Thinking, function; Time; Training; Training Programs; Translating; Trauma; Travel; Treatment Efficacy; trend; Ultrasonography; Uncertainty; Universities; university student; Upper arm; Week; Woman; Women`s Group; Work; Writing
Project start date: 2004-07-01
Project end date: 2011-06-30
Budget start date: 1-JUL-2008
Budget end date: 30-JUN-2011
PFA/PA: PAR-00-039
5K05CA096558-05 (2008): $128411
VALIDATION OF AN ANTIBODY TEST FOR EARLY DIAGNOSIS OF OVARIAN CANCER
A Michael, Dir, Molecular Bio / Human Gen, Prof.
Wayne State Universitycity: Detroit country: United States (us)
Grant 1R01CA160541-01 from National Cancer Institute
Abstract: When discovered at stage I ovarian cancer is curable in 90% of the cases using surgery and chemotherapy. There are 21,000 new cases per year of ovarian cancer however 75% of those cases are diagnosed at stage III or IV and their 5-year survival is about 20%. This results in about 14,000 deaths per year in the US. About 1 in 200 women in North America carries BRCA1 or BRCA2 mutations and 5 million women with a family history of ovarian cancer in a first or second degree relative. Women in these categories who are at higher risk of ovarian cancer would clearly benefit from a screening test and therefore represent the communities that would benefit from this project. A screening test for ovarian cancer will change the approach to healthcare delivery by reducing stage of ovarian cancer at diagnosis to stage at which it is more likely to be curable. We developed a high-throughput proteomics technology we call "Epitomics" for (epitope-omics) in which we immunoselect thousands of phage displayed antigens from cDNA libraries made from RNA from ovarian cancer tissue and cells. We used protein microarrays as a massively parallel immunoassay system to identify the proteins coded by the T7 bacteriophage cDNA libraries that bind to antibodies specifically in the serum of ovarian cancer patients and not to antibodies present in women with benign gynecological diseases. We propose to validate these biomarkers using in vitro synthesized proteins using immunoassays on Luminex bead arrays. Our hypothesis is that it requires panels of biomarkers to accurately distinguish patients with ovarian cancer from those with gynecological benign diseases. Most people in the biomarker field would agree with this hypothesis. We will synthesize proteins in vitro using PCR templates from our selected biomarker bacteriophage clones that we have shown are tumor antigens reacting with antibodies specifically in the serum of ovarian cancer patients. We will validate these biomarkers using sera from early and late stage ovarian cancer. In addition, to ensure the specificity of the diagnostic test we are developing we will assay these biomarkers against sera from women with benign gynecological diseases, autoimmune diseases, and women with other cancers. However, if a fraction of patients are still misclassified using these biomarkers we will use additional approaches such as full length recombinant proteins of the tumor antigens. If necessary alternative approaches will be pursued targeting autoantibodies that are formed against tumor antigens that are overexpressed or mutated by tumor cells. These approaches should provide us with a sufficiently robust panel of antigen biomarker analytes for a bead array assay for the early detection of ovarian cancer. The focus of this project is to translate our large scale immuno-proteomics discoveries of tumor associated antigens into Luminex bead array assays to detect serum autoantibodies for the detection of early stage cancer of the ovary in high risk women and women with a family history of ovarian cancer. The goal of this project is the final refinement of antigen biomarkers from a large scale proteomic screen so as to employ peptide antigens for the detection of ovarian cancer at an early stage. We are focusing on the most dangerous form of ovarian cancer serous adenocarcinoma, which is often diagnosed at a late stage that is difficult to treat successfully. A blood test to detect antibodies against cancer antigens is a laboratory format for a diagnostic test that can readily be implemented in a clinical setting in order to identify this disease at an early and 95% curable stage
Keywords: Amino Acid Sequence; Antibodies; antigen binding; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Bacteriophage T7; Bacteriophages; Benign; Binding (Molecular Function); Biological Assay; biomarker; Blood Tests; BRCA1 Mutation; BRCA2 Mutation; Cancer cell line; Cancer Control; Cancer Patient; cancer type; Categories; cDNA Library; Cells; Cessation of life; chemotherapy; Classification; Clinic; Clinical; clinical Diagnosis; Cloning Vectors; Code; cohort; Communities; Complementary DNA; Development; Diagnosis; Diagnostic Neoplasm Staging; Diagnostic tests; Disease; disorder control; Early Diagnosis; Ensure; Epitopes; Family history of; Genetic Transcription; Goals; health care delivery; high risk; High Risk Woman; Human; Immune system; Immunoassay; In Vitro; Laboratories; Length; Link; Malignant neoplasm of ovary; Malignant Neoplasms; Modeling; Mutate; neoplastic cell; North America; novel; Operative Surgical Procedures; Ovarian Serous Adenocarcinoma; overexpression; particle; Patients; Pelvic Inflammatory Disease; Peptides; Phage Display; Phase; Protein Microchips; Proteins; Proteomics; Recombinant Proteins; research study; response; RNA; Sampling; Screening for Ovarian Cancer; Screening procedure; Second Degree Relative; Sensitivity and Specificity; Serous Cystadenocarcinoma; Serum; Specificity; Stage at Diagnosis; Staging; Surface; System; Technology; Testing; Tissue Sample; Tissues; Training; Translating; Translations; tumor; Tumor Antigens; Tumor Tissue; Validation; Woman
Relevance: The goal of this project is the final refinement of antigen biomarkers from a large scale proteomic screen so as to employ peptide antigens for the detection of ovarian cancer at an early stage. We are focusing on the most dangerous form of ovarian cancer serous adenocarcinoma, which is often diagnosed at a late stage that is difficult to treat successfully. A blood test to detect antibodies against cancer antigens is a laboratory format for a diagnostic test that can readily be implemented in a clinical setting in order to identify this disease at an early and 95% curable stage
Project start date: 2011-08-17
Project end date: 2014-06-30
Budget start date: 17-AUG-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-10-067
1R01CA160541-01 (2011): $315400
EXTREME LONGEVITY FAMILY STUDY
A Michael, Professor Of Genetics
Washington Universitycity: Saint Louis country: United States (us)
Grant 5U01AG023746-07 from National Institute On Aging
Abstract: We will exploit the multicenter Long Life Family Study (LLFS), a unique resource for research on human longevity and healthy aging, to find genetic variants associated with these traits. In the current period, we successfully enrolled and extensively phenotyped 4,953 individuals in 539 two-generational families that demonstrate clustering for exceptional survival in the upper generation. Fewer than 1% of the Framingham Heart Study (FHS) families (a roughly random sample of families) would meet the minimal entrance criteria for exceptional survival required in the LLFS. Thus our least exceptional families show more clustering for exceptional longevity than 99% of the Framingham families. Further, the children´s generation have significantly lower rates of major diseases of aging including diabetes, chronic pulmonary disease, peripheral artery disease and show significantly more favorable profiles of quantitative mariners of healthy aging such as blood pressure, lipids, functional performance, and cognitive indices compared to FHS. These endophenotypes show greater clustering (with high heritability) in the LLFS familiesthan in FHS. Thus, LLFS has likely greatly enriched the prevalence of any gene variants for longevity and healthy aging endophenotypes, thereby increasing detection power. Most importantly, the family design of LLFS provides additional power and analytic opportunities to discover genetic influences than would be possible in a study of unrelated individuals, especially with regard to rare alleles. Our specific aims are to 1) continue phenotyping by assaying biomarkers of healthy aging on stored samples, annually tracking subjects for new significant medical and health events, and comparing Medicare (and Danish equivalent) disease and utilization data with reference samples; 2) identiy common genetic variants for healthy aging and excepional survival using GWAS; 3) identify rare variants for exceptional survival and healthy aging by targeted sequencing; and 4) more clearly dissect the genetic architecture of exceptional survival an healthy aging through a systems approach involving genet networks and pathways, to better understand the complex interplay between genetic variants, exposures, and covariates in the development of endophenotypes. Taking a multidisciplinary approach involving clinicians, demographers, geneticists, epidemiologists, and computational scientists, we propose to capitalize on the investments already made in creating this unique cohort to further our understanding of the nature of exceptional survival and healthy aging. Exceptional longevity and healthy aging are highly enriched in the families enrolled in the LLFS thus allowing us a unique opportunity to discover both common and rare genetic associations with these traits. Such associations will not only markedly enhance our understanding of why some people age so much better than others, but will also lead to enhanced prognostication for healthy and unhealthy aging and potentially disease prevention strategies
Keywords: Age; Aging; Alleles; Architecture; Biological Assay; biomarker; Blood Pressure; Cardiovascular system; Child; Chronic; Cognitive; cognitive function; cohort; Complex; Data; Demographer; design; Detection; Development; Diabetes Mellitus; Disease; disorder prevention; endophenotype; Enrollment; Epidemiologist; Event; Family; Family Study; Framingham Heart Study; gene environment interaction; gene interaction; Generations; Genes; Genetic; genetic association; genetic variant; Genets; genome wide association study; Health; healthy aging; Heritability; Human; Immune system; indexing; Individual; Inflammation; interdisciplinary approach; Investments; Lead; Life; Lipids; Longevity; Lung; Lung diseases; Medical; Medicare; meetings; Nature; Pathway interactions; Performance; Peripheral arterial disease; Phenotype; Physical Function; Prevalence; Prevention strategy; public health relevance; Resources; Role; Sampling; Scientist; System; Testing; trait; Variant; Variation (Genetics)
Project start date: 2004-08-15
Project end date: 2013-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-AG-10-005
5U01AG023746-07 (2011): $1742376
MOLECULAR DISSECTION OF CYTOKINESIS
A Michael, Associate Professor
University Of Chicagocity: Chicago country: United States (us)
Grant 5R01GM074743-04 from National Institute Of General Medical Sciences
Abstract: We seek to understand the molecular basis of cell division, cytokinesis, in animal cells. The central spindle, a set of antiparallel bundled microtubules in the anaphase spindle, regulates formation of the actomyosin- based contractile ring and is essential for completion of cytokinesis. We propose that the organization and function of the central spindle is a consequence of the structural organization and biochemical properties of the centralspindlin complex. Centralspindlin is an evolutionary conserved, multimeric complex containing a kinesin-like protein (ZEN-4/MKLP1) and a Rho family GAP (CYK-4/MgcRacGAP) that is highly concentrated on the central spindle and midbody during anaphase and telophase, respectively. We propose to combine in vitro biochemistry and in vivo rescue assays in C. elegans embryos and in mammalian cells to address three specific aims (1) To dissect the molecular organization of the centralspindlin complex and to characterize the atypical kinesin protein, ZEN-4. By characterizing the critical protein domains in the centralspindlin complex in relative isolation, we will develop the biochemical framework necessary to understand the function of these molecules in more complex reactions as well as in vivo. (2) To decipher the molecular mechanism of central spindle assembly. Central spindle assembly will be reconstituted in vitro from purified components in order to define the principles by which this set of dynamic components assemble into a highly ordered and stable structure. (3) To determine how the central spindle mediates completion of cytokinesis. Centralspindlin contains two distinct protein domains that are proposed to control late steps in cytokinesis. Therefore, the molecular function of these domains will be established. This research will provide molecular insights into a cellular structure that is critical for cell multiplication. Therefore our research could contribute to the development of novel anti-mitotic agents for the treatment of cancer. Furthermore, molecular dissection of ZEN-4 will enhance our understanding of the mechanism of action of microtubule motors
Keywords: 4-3 Hydrophobic Repeat; Abscission; Actomyosin; Address; Adenosine Triphosphatase; Adenosinetriphosphatase; Anaphase; Animals; anticancer therapy; Assay; ATP phosphohydrolase; ATPase; aurora B kinase; base; Binding; Binding (Molecular Function); Bioassay; Biochemical; Biochemistry; Biologic Assays; Biological Assay; C elegans; C.elegans; Caenorhabditis elegans; cancer therapy; Cancer Treatment; Cell Components; Cell division; Cell Division Process; Cell Growth in Number; Cell Isolation; Cell Multiplication; Cell Proliferation; Cell Segregation; Cell Separation; Cell Separation Technology; cell sorting; Cell Structure; Cells; Cellular Proliferation; Cellular Structures; Chemistry, Biological; Coiled-Coil Domain; Complex; Cytokinesis; Cytoplasmic Division; daughter cell; Defect; Development; DISSEC; Dissection; Ectopic Expression; Embryo; Embryonic; Excision; experiment; experimental research; experimental study; Extirpation; Factor Analyses; Factor Analysis; Family; functional loss; gene product; Genetic Screening; Goals; In Vitro; in vivo; insight; Investigators; Kinesin; language translation; Left-Handed Twist; Locomotor Activity; male germ cell racGAP; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Mammalian Cell; Measures; Mediating; member; mgcRacGAP; Micro-tubule; Microtubule Bundle; Microtubules; Mitotic; Mitotic Anaphase; Mitotic spindle; Molecular; Molecular Interaction; Molecular Machines; Motor; Motor Activity; novel; Peptide Domain; Play; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; progenitor; programs; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; protein complex; Protein Domains; Proteins; Quelling; Reaction; Recombinants; reconstitute; reconstitution; Relative; Relative (related person); Removal; Research; Research Personnel; research study; Researchers; resection; rho; rho GTPase-activating protein; rhoGAP; RNA Interference; RNA Silencing; RNA Silencings; RNAi; Role; Sequence-Specific Posttranscriptional Gene Silencing; social role; Structure; Surgical Removal; System; System, LOINC Axis 4; telophase; Tertiary Protein Structure; Translating; Translatings
Project start date: 2006-07-01
Project end date: 2011-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2011
5R01GM074743-04 (2009): $286755
P-1: IMMUNOTHERAPY OF PANCREATIC ADENOCARCINOMA
A Michael, Professor
University Of Nebraska Medical Centercity: Omaha country: United States (us)
Abstract: We propose to further develop and test novel reagents that can be used for immunotherapy of human adenocarcinomas, particularly those of the pancreas. The reagents under development in this project include highly specific murine monoclonal antibodies to circulating tumor-associated antigens (TAA), which form immune complexes that are taken up by dendritic cells (DCs) and other antigen-presenting cells (APCs) and are efficiently presented to the immune system. As a result, humoral and cellular immune responses against TAA are activated. The fundamental hypothesis under investigation is that murine antibodies against circulating human tumor antigens will bind to those antigens when administered to patients, form immune complexes that will be bound to APCs either directly or subsequent to the development of human anti-mouse antibody (HAMA) responses that capture these complexes, and that antigen processing by the APCs will produce immune responses against the targeted antigen. We specifically hypothesize that the anti-MUC1 antibody BrevaRex¿ MAb-AR20.5, when combined with soluble and/or cell-bound MUC1 in patients, will induce humoral and cellular immune responses to MUC1 that will be protective against pancreatic cancer in patients with MUC1 -expressing pancreatic and other tumors. The strategy has the unique capacity to provide a method of vaccinating each patient with their own tumor antigens through in vivo capture and presentation of circulating and cell associated tumor antigens. We will target the cell surface associated mucin MUC1 with BrevaRex¿ MAb-AR20.5, a murine IgGlK specific for the tandem repeat region of MUC1, which should provide effective targets for cell mediated responses against the tumor cells that produced the circulating antigen. One important challenge of producing effective tumor vaccines is developing reagents that break immunological tolerance to tumor-associated antigens. For preclinical studies, will utilize an inbred mouse strain on the C57BL/6 background that expresses human MUC1 in the correct temporal and spatial pattern (MUC1 Tg), develops tolerance and is refractory to immunization with MUC1. This experimental model has enabled us to study the effect of endogenous expression of the MUC1 gene on the ability of mice to produce protective immune responses to tumors, and represents an improved model system for evaluating the efficacy of anti-MUC1 formulations in vivo within the context of existing tolerance. We have developed and investigated a model in which a murine pancreatic tumor (Panc02) syngeneic to C57BL/6 transfected with human MUC1 (Panc02.MUC1), can be transplanted subcutaneously and orthotopically. In the studies proposed here, we will evaluate the mechanism of action of BrevaRex¿ MAb-AR20.5 in the murine model, conduct preclinical studies to determine its mechanism of action, and investigate the utility of combining this therapy with other interventions in a clinical trial in humans with pancreatic cancer
Keywords: Adenocarcinoma; Adjuvant; Animal Model; Antibodies; Antibody Formation; antigen processing; Antigen Targeting; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Binding (Molecular Function); Biological Models; cancer therapy; Cancer Vaccines; Cell surface; Cells; Clinical Trials; Combined Modality Therapy; Complex; Dendritic Cells; Development; Dose; Drug Formulations; Effectiveness; effectiveness measure; Experimental Designs; Experimental Models; Goals; Human; Human Anti-Mouse Antibody; Immune; Immune response; Immune system; Immunity; Immunization; immunogenicity; Immunotherapy; improved; in vivo; Inbred Strains Mice; Individual; Intervention; Investigation; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Mediating; Methods; Modeling; Monoclonal Antibodies; MUC1 gene; Mucin-1 Staining Method; Mucins; Mus; neoplastic cell; novel; Pancreas; Pancreatic Adenocarcinoma; pancreatic neoplasm; Pathway interactions; Patients; Pattern; Phase II Clinical Trials; preclinical study; Production; Property; Reagent; Refractory; research clinical testing; Resectable; response; Schedule; Tandem Repeat Sequences; Testing; Transgenic Mice; Translating; Transplantation; tumor; Tumor Antigens; Tumor Cell Line; tumor growth; Vaccinated
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5P50CA127297-04_0001 (2011): $128842
INTERDISCIPLINARY VISION TRAINING PROGRAM
A Michael, Professor
Brown Universitycity: Providence country: United States (us)
Grant 5T32EY018080-05 from National Eye Institute
Abstract: We propose the establishment of an Interdisciplinary Pre-doctoral Training Program in Vision at Brown University. This training program will constitute a key component of the Brown´s new Center for Vision Research, under the auspices of the interdisciplinary Brain Science Program. The central objective of this Vision Training Program (VTP) is to provide specialized training in vision to graduate students already matriculating in the Neuroscience or Cognitive and Linguistic Sciences graduate programs. We propose supporting 3 students per year; students will receive VTP support starting in their 2nd graduate year. The VTP will complement and supplement the basic course requirements of the graduate programs from which individual students come. We will provide broad, multi-disciplinary training at all levels with a strong foundation in core concepts, skills, methodologies, and advanced comprehension of the scientific literature. In general, we foster an environment unconstrained by traditional discipline boundaries and where graduate students are encouraged to work at the interfaces of these disciplines. At all stages of instruction, we will integrate skills considered essential for successful, independent research careers in vision research. These include critical thinking and reasoning, effective science writing and oral presentation, knowledge of scientific review processes, and training in ethics. Students will participate in new initiatives to ensure exposure of graduate students to clinical and disease concepts; these experiences will help students identify the scientific problems that are most relevant to improving human health. The proposed training program has 10 participating faculty members, drawn from 5 departments. These faculty members currently mentor 22 graduate students engaged in vision research. Overall, vision research at Brown includes 27 faculty members in 9 departments; research interests include biological vision, machine vision, and computation. To ensure a successful training program, we have selected a core training faculty engaged in the study of biological vision with a strong training record. However, trainees will benefit from interactions with the entire vision community at Brown. Relevance Eye diseases afflict 26.8 million Americans age 40 and older, according to recent estimates, and that number will grow as the population ages. Innovations in understanding the biology of the human visual system and devising novel strategies to prevent, treat, or compensate for vision loss will come from a new generation of researchers trained to synthesize information gleaned from a variety of approaches and disciplines. We aim to train this kind of researcher and bring further cohesion to the diverse vision research community at Brown
Keywords: Training Programs; Vision
Project start date: 2007-04-01
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-02-109
5T32EY018080-05 (2011): $93686
MECHANISMS OF INTESTINAL STEM CELL EXPANSION FOLLOWING RESECTION
A Michael, Professor - Faculty
Children´s Hospital Medical Center Cincicity: Cincinnati country: United States (us)
Grant 5R01DK083325-04 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: We developed a mouse model of ileo-cecal resection (ICR) and used new and traditional approaches to define cellular mechanisms mediating adaptive intestinal growth to compensate for the intestinal loss. These mechanisms include a brief period of expansion of intestinal stem cells (ISC) immediately after ICR, followed by marked increases in crypt fission, and crypt number which mediate increases in mucosal surface area. Recent reports suggest that there may be two populations of ISC a slowly cycling quiescent-ISC pool (q-ISC) located above Paneth cells (Upper Stem cell Zone, USZ) and a more rapidly cycling active-ISC pool (a-ISC) of crypt base columnar cells (CBC) marked by the expression of Lgr5. A complete understanding of the adaptive response will require analysis of these putative ISC sub-populations. Our preliminary studies demonstrate increased intestinal IGF-I expression during the period of ISC expansion after ICR. Glucagon-like peptide-2 (GLP-2) augmented the observed ISC expansion and local IGF-I expression, but only if given immediately following resection. In the clinical setting many patients are unable to tolerate enteral nutrition (EN) after massive intestinal loss, and require total parenteral nutrition (TPN). The increased incidence of chronic short bowel syndrome (SBS) in these patients suggests that TPN-feeding may attenuate the normal adaptive ISC expansion. The current proposal examines 3 hypotheses; 1. Following ICR, q- ISC and a-ISC show distinct kinetics, as recruitment of q-ISC will precede expansion of a-ISC. 2. IGF-I expression and signaling is required for normal ICR-induced expansion and mediates GLP-2 effects after ICR. Constitutive IGF-I expression will enhance and prolong ISC expansion following ICR. 3. EN drives IGF-I induced ISC expansion following ICR, but in TPN-fed mice GLP-2 will induce local IGF-I and restore ISC expansion following ICR. The following SA will test these hypotheses; SA1. Use the Lgr5-LacZ mouse to define whether ICR induces expansion of Lgr5/LacZ-positive a-ISC and how this relates to the process of crypt fission. Additional studies will validate the temporal expansion of a-ISC and q-ISC following ICR by defining the time course of label retention in the USZ and CBC regions after continuous thymidine analogue labeling. SA2. Study ISC expansion and crypt fission following ICR in transgenic mice with constitutive over-expression of IGF-I or impaired IGF-I signaling. Characterize expansion of ISC in mice with attenuated IGF-IR signaling following ICR + GLP-2. SA3. Randomize the route of providing nutrition to mice following ICR to EN 1 GLP-2 vs. TPN 1 GLP-2. Assess the influence of the route of nutrition and administration of GLP-2 on both intestinal expression of IGF-I and normal ISC expansion following resection. Surgical loss of the intestine due to injury or disease may result in the inability to absorb enough liquid and food to survive. Fortunately, the remaining intestine is often able to compensate for this intestinal loss over time. When it cannot, people must receive both fluids and nutrition intravenously. Research outlined in this proposal will help us better understand how the cells that continually renew the lining of the intestine every day (intestinal stem cells) increase in number to help compensate following intestinal loss
Keywords: analog; Area; Attenuated; Award; base; Cell Proliferation; Cells; Chronic; Clinical; Columnar Cell; Disease; Enteral Nutrition; Excision; feeding; Food; Funding; glucagon-like peptide; Growth; Growth Factor; Health; Incidence; Injury; insight; Insulin-Like Growth Factor I; Intestines; Kinetics; Knowledge; Label; LacZ Genes; Liquid substance; Mediating; Modeling; mouse model; Mus; nutrition; Operative Surgical Procedures; Paneth Cells; Patients; Population; Process; Randomized; Reporting; Research; research study; response; Route; self-renewal; Short Bowel Syndrome; Signal Transduction; stem cell biology; Stem cells; Surface; Testing; Therapeutic; Thymidine; Time; Total Parenteral Nutrition; Transgenic Mice; Work
Relevance: NARRATIVE Surgical loss of the intestine due to injury or disease may result in the inability to absorb enough liquid and food to survive. Fortunately, the remaining intestine is often able to compensate for this intestinal loss over time. When it cannot, people must receive both fluids and nutrition intravenously. Research outlined in this proposal will help us better understand how the cells that continually renew the lining of the intestine every day (intestinal stem cells) increase in number to help compensate following intestinal loss
Project start date: 2009-07-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01DK083325-04 (2011): $264347
PROGERIN ENDOTHELIAL DYSFUNCTION AND VASCULAR DISEASE
A Michael, Professor And Chairman
Brigham And Women´s Hospitalcity: Boston country: United States (us)
Grant 5R01AG032443-02 from National Institute On Aging
Abstract: Vascular diseases, in particular atherosclerosis and its complications (e.g., myocardial infarction and stroke), continue to be a major public health problem that afflicts millions of people in the United States and other countries. Given their inherently complex and variable nature, the study of monogenic forms of some types of vascular disease (e.g., familial hyperlipidemias and atherosclerosis) can greatly assist in elucidating their pathogenesis. The recent discovery of the genetic basis of Hutchinson-Gilford Progeria Syndrome (HGPS) provides such an opportunity. HGPS is a premature aging disorder in which affected children have normal appearance at birth, but begin to age rapidly within 1-2 years. This disease affects multiple organ systems, including the heart and blood vessels. Indeed, the most prominent and fatal feature of HGPS is premature and accelerated atherosclerosis resulting in heart attacks and strokes. HGPS is caused by a single point mutation in the LMNA gene, which results in accumulation of a mutant form of the lamin A protein called Progerin. The central hypothesis of this project is that Progerin accumulation in vascular endothelium results in chronic endothelial dysfunction, contributing to the onset of vascular pathologies documented in patients with HGPS, and potentially also in normal individuals with aging. In the first specific aim, we will dissect the molecular pathways activated in Progerin-expressing cultured EC that lead to chronic endothelial dysfunction. In the second specific aim, we will elucidate the paracrine effects that endothelial-derived, Progerin- stimulated mediators (such as interleukin-1) exert on vascular smooth muscle cells. In the third specific aim, we will investigate the pathophysiological consequences of endothelial-specific expression of Progerin in vivo in a novel transgenic murine model. These studies should provide important mechanistic insights into the cellular and molecular causes of vascular disease in HGPS patients, and may suggest new therapeutic strategies for other vascular diseases in which endothelial dysfunction plays a pathogenic role. Several human diseases are associated with aging; among these are atherosclerosis and its consequences, heart attacks and strokes. Children with a genetic mutation in a specific gene develop a syndrome of premature aging called Progeria. They develop atherosclerotic plaques, and are prone to heart attacks and strokes. We propose to understand how this mutation triggers the development of cardiovascular disease in children with Progeria. Results from these studies, involving a specific gene linked to the development of vascular disease, will hopefully indicate new ways to treat children with Progeria and may also lead to innovative strategies to diagnose, prevent, and treat heart disease in the general population
Keywords: Affect; Age; Aging; Aging-Related Process; Anti-inflammatory; Anti-Inflammatory Agents; Appearance; Arterial Fatty Streak; Arteries; Atherosclerosis; autocrine; base; Birth; Blood Vessels; body system; Cardiovascular Diseases; Cell physiology; Cells; Child; Chronic; Complex; Country; Defect; defined contribution; design; Development; Diagnosis; Disease; Documentation; Endothelial Cells; Event; Functional disorder; Future; Gene Expression; Gene Mutation; General Population; Genes; Genetic; genome-wide; Goals; Heart; Heart Diseases; Human; human disease; Hyperlipidemia; Impairment; In Vitro; in vitro Model; in vivo; in vivo Model; Individual; innovation; insight; Interleukin-1; Investigation; Laboratories; Lamin Type A; Lead; Link; Maintenance; Medial; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; mouse model; Mus; mutant; Mutation; Myocardial Infarction; Natural History; Nature; novel; novel therapeutics; Nuclear Lamina; overexpression; paracrine; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Play; Point Mutation; premature; Premature aging syndrome; prevent; Progeria; programs; Proteins; public health medicine (field); public health relevance; Research; research study; response; Role; Signal Pathway; Signal Transduction Pathway; Smooth Muscle Myocytes; stroke; Syndrome; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Translating; United States; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vascular remodeling; Viral; Work
Relevance: "PROGERIN, ENDOTHELIAL DYSFUNCTION, AND VASCULAR DISEASE" Several human diseases are associated with aging; among these are atherosclerosis and its consequences, heart attacks and strokes. Children with a genetic mutation in a specific gene develop a syndrome of premature aging called Progeria. They develop atherosclerotic plaques, and are prone to heart attacks and strokes. We propose to understand how this mutation triggers the development of cardiovascular disease in children with Progeria. Results from these studies, involving a specific gene linked to the development of vascular disease, will hopefully indicate new ways to treat children with Progeria and may also lead to innovative strategies to diagnose, prevent, and treat heart disease in the general population
Project start date: 2010-09-01
Project end date: 2015-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-07-070
5R01AG032443-02 (2011): $317185
1R01AG032443-01A2 (2010): $329171
MICROBICIDE PROPERTIES OF RT INHIBITOR COMBINATIONS
A Michael, Professor
University Of Pittsburgh At Pittsburghcity: Pittsburgh country: United States (us)
Grant 5R33AI079801-04 from National Institute Of Allergy And Infectious Diseases
Abstract: Topical microbicides are an important strategy to minimize heterosexual transmission of HIV. Several single agent microbicides are in clinical trials, including one based on the nonnucleoside reverse transcriptase inhibitor (NNRTI) UC781 that we discovered as a potential microbicidal agent. However, combination microbicides may be preferable, yet only a single combination microbicide is currently under evaluation. There is also an urgent need to identify new pipeline microbicidal agents. We have found that the nucleoside RT inhibitor (NRTI) 4´-ethynyl-2-fluoro-deoxyadenosine (4´E-2FdA) provides a potent and prolonged barrier to HIV- 1 infection of cells in the subsequent absence of exogenous drug, a property previously only noted for NNRTI such as UC781. The "memory effect" barrier is imparted by 4´E-2FdA at drug levels orders of magnitude less than those needed for protection by the nucleotide tenofovir, currently in clinical assessment for microbicide use. We hypothesize that microbicides comprising combinations of different classes of highly potent RT inhibitors, namely the NNRTI UC781 and an NRTI such as 4´E-2FdA, will provide an optimal barrier to HIV-1 transmission. We therefore propose these Specific Aims for this R21/R33 phased innovation application R21 Aim 1. To evaluate the in vitro (cell-based) microbicidal properties of NRTI and UC781 alone and in combination. These studies include assessment of antiviral activity and "memory effect" protection imparted by NRTIs and UC781 alone and in combination using primary cells (PBMCs, CD4+ T-cells, macrophages) and different HIV drug-sensitive and drug-resistant strains, isolates and clades. R21 Aim 2. To elucidate the mechanism of 4´E-2FdA (and analogs) induced protective barrier or "memory effect" in HIV susceptible cells. These studies include characterization of uptake, conversion to triphosphate and intracellular stability of the NRTI-TPs, as well as detailed kinetic evaluations of the NRTI substrate activity with enzymes involved in metabolism of the NRTIs. R21 Deliverables Identification of a lead NRTI and two back-ups for use with UC781 for development as a combination microbicide. R33 Aim 1. To formulate the NRTI/NNRTI combinations selected in the R21 phase into an appropriate delivery system for vaginal topical use. NRTIs and NNRTIs have different chemical properties, thus appropriate delivery systems must be identified to enable incorporation and release of the active agents. We will prepare and evaluate both gel and rapidly dissolving film formulations for the combination microbicide. R33 Aim 2. To evaluate the anti-HIV microbicidal activity of formulated NRTI/NNRTI combinations in an ex vivo cervical explant tissue model. These studies will use a newly developed physiologically relevant polarized cervical tissue model to assess the impact of formulated microbicides alone and in combination on HIV transmission and infectivity. R33 Deliverables Identification of an appropriate delivery formulation for the selected NRTI/NNRTI combination for entry into subsequent preclinical safety and efficacy studies
Keywords: analog; anti-HIV microbicide; Antiviral Agents; Back; base; CD4 Positive T Lymphocytes; Cells; Cervical; chemical property; Clinical assessments; Clinical Trials; cost effective; Deoxyadenosines; design; Development; Disease; Drug Formulations; Drug resistance; Drug-sensitive; Economics; Educational process of instructing; Enzymes; Equilibrium; Evaluation; Film; Gel; Gender; Generations; Half-Life; Heterosexuals; HIV; HIV drug resistance; HIV Infections; HIV vaccine; HIV-1; In Vitro; Inequality; Infection; inhibitor/antagonist; innovation; Kinetics; Lead; Local Microbicides; macrophage; Mediating; Memory; Metabolism; microbicide; non-nucleoside reverse transcriptase inhibitors; novel; Nucleosides; Nucleotides; Pharmaceutical Preparations; Phase; Poliomyelitis; preclinical efficacy; preclinical safety; prevent; Property; research clinical testing; resistant strain; Risk; Sexual Transmission; Smallpox; success; System; Systemic Therapy; Tenofovir; Tissue Model; topical antiviral; transmission process; tripolyphosphate; UC 781; uptake; Vaccines; Vagina; Variant; Virion; Virus; Woman
Relevance: This project seeks to develop anti-HIV microbicides based on the non-nucleoside RT inhibitor UC781 in combination with novel 4´-substituted nucleosides, a combination found to provide profound and protracted protection of susceptible cells against HIV infection in vitro. Our studies will provide potent new formulations to the microbicide development pipeline for entry into clinical evaluation
Project start date: 2008-09-10
Project end date: 2013-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5R33AI079801-04 (2011): $450168
Sponsored Links Excellgen http://Excellgen.com
ASSAYS FOR SCREENING HISTONE MODIFICATIONS IN CANCER
A Michael, Associate Professor
Ohio State Universitycity: Columbus country: United States (us)
Grant 5R01CA107106-06 from National Cancer Institute
Abstract: To better understand the role of histone variants and their post-translational modifications on the development, progression and treatment of chronic lymphocytic leukemia (CLL), we intend to develop and apply high mass accuracy mass spectrometry based assays to profile CLL-specific patterns of histone isoforms and conduct detailed molecular characterization to identify the specific histone isoforms present in different genetic subtypes of CLL and their impact on patient treatment and outcome. We will carry out these goals by profiling the state of histone modifications and characterize the changes in histone modifications that are induced by treatment with chromatin remodeling reagents and changes that are associated with specific genetic mutations. We will focus on processes that correlate with induction of apoptosis and differentiation in vitro and in vivo in CLL cells. The rationale is to define the changes in chromatin induced by these therapies and determine chromatin´s potential to predict risk and outcome for the therapy. The techniques developed and validated in this proposal will allow basic scientists to detect and understand specific changes observed in histone isoforms and clinical-translational scientists to effectively predict outcome and apply therapies that modify histones in patients with CLL. The aims of this application are Aim 1. To combine multidimensional liquid chromatography with high-mass accuracy mass spectrometry to profile histone proteins and characterize histone protein isoforms in primary malignant hematopoietic tumor cells. These techniques will be applied to profile malignant cells from genetic subtypes of CLL. We hypothesize these techniques will facilitate the characterization of histone variants and post-translational modifications and permit the targeting of specific CLL-specific sites not identifiable with currently available immunological techniques; Aim 2. Obtain the histone profiles of CLL patients and determine the clinical relevance of these profiles relative to other biomarkers used to predict early progression of this disease. We hypothesize that the application of LC-MS based histone profiling will lead to new markers that will facilitate the stratification of CLL patients according to risk; and Aim 3. To identify, map and characterize sites of histone post-translational modifications in malignant cells from CLL subtypes by high- mass accuracy liquid chromatography tandem mass spectrometry. We will determine the histone H1 phosphorylation isoforms present in nuclear and cytosolic extracts due to H1 release induced by flavopiridol therapy in CLL patients. We hypothesize that proteomics will allow the identification of select histone modifications that will serve as markers for mechanistic endpoints and patient outcome in flavopiridol therapy of CLL patients. Core histones play a vital role in the regulation of cellular processes that involve access to chromosomal DNA and subsequent gene transcription. These processes are misregulated in a large proportion of cancers including chronic lymphocytic leukemia (CLL). To better understand the role of histone variants and their post- translational modifications on the development, progression and treatment of CLL, we intend to develop and apply high mass accuracy mass spectrometry based assays to profile CLL-specific patterns of histone isoforms and conduct detailed molecular characterization to identify the specific histone isoforms present in different genetic subtypes of CLL and their impact on patient treatment and outcome
Keywords: Age; base; Biological Assay; biomarker; cancer cell; Cell physiology; Cells; Chromatin; chromatin remodeling; Chronic Lymphocytic Leukemia; Clinical; clinically relevant; Development; Disease; Disease Progression; DNA; early onset; Enzymes; Epigenetic Process; flavopiridol; Gender; Gene Mutation; Genetic; Genetic Transcription; Goals; Hematopoietic Neoplasms; Histone H1; Histone H1(s); histone modification; Histones; Immunologic Techniques; Immunophenotyping; In Vitro; in vivo; Induction of Apoptosis; Lead; leukemia; Liquid Chromatography; Malignant - descriptor; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Methods; Molecular; novel marker; Nuclear; Outcome; Patients; Pattern; Phosphorylation; Play; Post-Translational Protein Processing; Process; Prognostic Marker; Protein Isoforms; protein profiling; Proteins; Proteomics; public health relevance; Reagent; Regulation; Relative (related person); Research; response; Risk; Role; Sampling; Scientist; Screening procedure; Site; Staging; Stratification; tandem mass spectrometry; Techniques; therapy outcome; Tissue Banking; Tissue Banks; Treatment outcome; tumor; Variant; ZAP-70 Gene
Relevance: Core histones play a vital role in the regulation of cellular processes that involve access to chromosomal DNA and subsequent gene transcription. These processes are misregulated in a large proportion of cancers including chronic lymphocytic leukemia (CLL). To better understand the role of histone variants and their post- translational modifications on the development, progression and treatment of CLL, we intend to develop and apply high mass accuracy mass spectrometry based assays to profile CLL-specific patterns of histone isoforms and conduct detailed molecular characterization to identify the specific histone isoforms present in different genetic subtypes of CLL and their impact on patient treatment and outcome
Project start date: 2004-09-01
Project end date: 2014-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01CA107106-06 (2011): $226740
THYROID HORMONE CONTROL OF MYOCARDIAL METABOLISM IN AGING
A Michael
Seattle Children´s Hospitalcity: Seattle country: United States (us)
Grant 5R21AG033815-02 from National Institute On Aging
Abstract: Thyroid hormone regulates cardiac function through binding to its nuclear receptors (TRs). Classically, the ligand bound receptors in turn bind to response elements and control transcription of key cardiac genes. A decrease in triiodothyronine-TR binding, such as occurs in systemic hypothyroidism, certain resistance to thyroid hormone syndromes (RTH), or in various transgenic mouse models adversely effects cardiac function. Changes in TR ligand binding capacity have also been reported in failing human hearts. Although, this cardiac dysfunction occurs in part through alterations in excitation-contraction and transport proteins, the data from our laboratory indicate that thyroid hormone also mediates changes in myocardial energy metabolism. Thyroid receptor dysfunction may limit the heart´s ability to shift substrate pathways and provide adequate energy supply during stress responses. Chronic or intermittent energy starvation during these stress periods could contribute to abnormal compensatory processes and/or cardiomyocyte damage. Recent data from other laboratories indicate that exercise training in aged rats promoted improved cardiac function in association with elevated expression and binding capacity of thyroid hormone receptors. Exercise conditioning in these aged rats alters the mRNA expression for TR regulated genes such as myosin heavy chain alpha and beta, and sarcoplasmic reticulum in a manner suggesting mediation by thyroid hormone. Presumably, thyroid mediated signaling pathways triggered by exercise conditioning return senescent heart function to levels similar to those measured in much younger hearts. These data strongly imply that thyroid receptor dysregulation participates in cardiomyopathy associated with some states in the aged, such as subclinical hypothyroidism. Changes in metabolic signaling pathways might explain why the aging rat heart lacks the ability to modify substrate uptake in response to varying nutritional conditions. In particular, increasing fatty acid supply does not inhibit glucose uptake, suggesting that the myocardial ¿-oxidation capability is limited by aging, and that the aging heart´s substrate oxidative capacity restricts responses to stress or exercise. Thus, alterations in myocardial remodeling triggered by thyroid hormone signaling in aged hearts may be caused primarily by changes in metabolism. We have fully characterized myocardial metabolism in a transgenic mouse expressing a dominant negative cardiac selective mutation in TR¿1 and documented abnormal fatty acid metabolism in heart of aged non-transgenic littermates. We will use an aging mouse model, which manifests mild reductions in plasma total T3 levels to test the primary hypothesis that thyroid hormone mediates the metabolic phenotype in the aging heart. The proposed studies in response to PA-08-38 (Thyroid in Aging) will establish the basis for further studies, which would examine the molecular mechanisms of thyroid action, and determine if metabolic action by thyroid hormone can modify the cardiomyopathy of aging. This proposal is in response to PA-08-308 "Thyroid in Aging". We will evaluate thyroid hormone´s role in controlling substrate (fuel) use in the aging heart. These studies will serve as background data for more elaborate mechanistic studies in the future
Keywords: aged; Aging; base; Binding (Molecular Function); biological adaptation to stress; Cardiac; Cardiac Myocytes; Cardiomyopathies; Carrier Proteins; Chronic; conditioning; Data; Dominant-Negative Mutation; Energy Metabolism; Energy Supply; Exercise; fatty acid metabolism; Fatty Acids; Functional disorder; Future; Genes; Genetic Transcription; glucose uptake; Heart; heart function; Human; Hypothyroidism; improved; Laboratories; Ligand Binding; Measures; Mediating; Mediation; Metabolic; Metabolism; Molecular; mouse model; mRNA Expression; Mutation; Myocardial; Myosin Heavy Chains; Nuclear Receptors; Nutritional; oxidation; Pathway interactions; Phenotype; Plasma; Process; public health relevance; Rattus; receptor; receptor binding; Reporting; Resistance; response; Response Elements; Role; Sarcoplasmic Reticulum; senescence; Signal Pathway; Signal Transduction; Starvation; Stress; Syndrome; Testing; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Training; Transgenic Mice; Triiodothyronine; uptake; Ventricular Remodeling
Project start date: 2010-04-01
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-08-038
5R21AG033815-02 (2011): $179888
NIKON A1R CONFOCAL LASER SCANNING MICROSCOPE
A Michael, Associate Professor
Baylor College Of Medicinecity: Houston country: United States (us)
Grant 1S10RR027783-01A1 from National Center For Research Resources
Abstract: This request from a long-standing Baylor College of Medicine (BCM) microscopy core is for a new, fully-automated, state-of-the-art Nikon A1 laser scanning confocal microscope to replace an aging confocal system. The requirements include being able to provide (i) high resolution imaging at wavelengths covering the near UV, visible and near IR spectral range using both conventional and spectral imaging detectors; (ii) long-term time-lapse imaging with automatic focus and controlled gas/temperature; (iii) high-speed confocal imaging to track dynamic events in X and Y, and perform rapid Z-series acquisition at sequential time points (4D imaging); (iv) combining fast, accurate and repeatable autofocus and XYZ positioning control to allow 2D and 3D imaging at multiple locations in single to 96/384-well plate formats for high-speed, high- resolution imaging of fixed or live specimens; and, (v) enough flexibility and reliability (multiple wavelengths, conventional and spectral, and multiple locations) for true multidimensional confocal imaging controlled by user-friendly software. Long-term in-house demonstration of the Nikon A-1 has demonstrated its ability fulfill these requirements and those of the diverse experimental plans of a well-defined group of NIH-supported investigators. The system will be housed and managed by the Integrated Microscopy Core (IMC), the only fully-open-access imaging facility at BCM, and will synergize with and extend current automated microscopy resources, including hardware/software training and assay development support
Keywords: Aging; assay development; college; Computer software; Event; flexibility; Gases; Housing; Image; imaging detector; Lasers; Life; Location; Medicine; Microscope; Microscopy; Positioning Attribute; Research Personnel; Resolution; Resources; Scanning; Series; Specimen; Speed (motion); System; Temperature; Three-Dimensional Imaging; Time; Training; United States National Institutes of Health; user friendly software
Project start date: 2011-05-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PAR-10-082
1S10RR027783-01A1 (2011): $431422
TRAJECTORIES OF QOL IN PROSTATE CANCER SURVIVORS USING GROWTH CURVE MODELING
A Michael, Associate Professor Of Urology
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 5R21CA124786-02 from National Cancer Institute
Abstract: This proposal is in response to PA-04-034 "Exploratory Grants for Behavioral Research in Cancer Control." We propose to apply Growth Curve Analyses (GCA) to an existing dataset with longitudinal assessments of disease-specific and general quality of life (QOL) domains and psychological functioning of patients diagnosed with localized prostate cancer. Compared to a conventional multivariate approach, GCA provides a better way to examine individual change, explore correlates of change, and detect group differences in the process of change. GCA will identify trajectories of urinary and sexual functioning, general QOL, and psychological responses over time. These trajectories of functioning will provide a close approximation of a patient´s actual experience following treatment. Such information can be used by clinicians to realistically prepare patients for possible treatment related side-effects including the timeframe when such side-effects might occur or subside. Ultimately, results can be used to identify at-risk patients for dysfunction, who then can be targeted for preparatory interventions. The three-year data set (N = 986 at baseline; n = 664 at 36 months; 67.3% retention) consists of six assessments of urinary and sexual functioning, general QOL(FACT-P) and extensive assessments of depression, anxiety, negative moods, and intrusive and avoidant ideation. Sensitivity analyses and imputation methods will be used to address potential biases in the data due to patient drop-out and missing data. The specific aims are 1) To quantify trajectories of individual change in urinary and sexual functioning, QOL, and psychological functioning among prostate cancer survivors over 36 months; 2) to examine how these trajectories correlate with time invariant factors (e.g., treatment received, Gleason score, age); 3) to examine how trajectories of change in sexual and urinary function are associated with trajectories of change in QOL and psychological functioning; 4) to identify subgroups of patients with similar trajectories of sexual and urinary functioning. We hypothesize 1) that urinary and sexual dysfunction will be associated with lower levels of general QOL and psychological functioning over time; and 2) that subgroups of patients with similar trajectories of functioning exhibit distinct profiles or signatures characterized by clinical (i.e., urinary and sexual functioning) and psychological functioning (i.e., depression, intrusive and avoidant ideation). The proposed research is clinically significant in two ways 1) identifying trajectories of functioning provides new information to health care providers of how urinary and sexual symptoms might develop over time; and 2) subgroups with similar demographic, clinical, and psychological profiles might be targets for interventions designed to prepare patients to anticipate treatment related side effects. The proposed project is significant to public health for four main reasons 1) The examination of trajectories of symptom experience and quality of life over time among prostate cancer patients is an unexplored area. 2) The information gained from the analyses can be used by clinicians to realistically prepare patients for possible treatment related side-effects including the time frame when such side-effects might occur or subside. 3) Results can be used to identify patients who might be at risk for dysfunction, who subsequently might be targeted for preparatory interventions. 4) The proposed analyses use data from an already existing data set, thus making this application a cost-effective approach to obtain new information and knowledge
Keywords: Accounting; Address; Adverse effects; Affect; Affective; After Care; After-Treatment; Aftercare; Age; Analysis of Variance; ANOVA; anticancer therapy; Anxiety; Area; base; Behavioral Research; bowel; Cancer Control; Cancer Control Science; Cancer of Prostate; Cancer Patient; Cancer Survivor; Cancer Survivorship; cancer therapy; Cancer Treatment; Characteristics; Clinical; Clinical Evaluation; clinical significance; clinical test; Clinical Testing; clinically significant; cognitive function; Consultations; cost; Cross Sectional Analysis; Cross-Sectional Analyses; Cross-Sectional Studies; Cross-Sectional Survey; Data; Data Set; Dataset; depression; Development; Diagnosis; Diagnostic; Disease; Disease Frequency Surveys; disease/disorder; Disorder; Doctor of Philosophy; Drops; Dysfunction; Emotional; Exhibits; experience; Fatigue; Feeling; feelings; Functional disorder; Generalized Growth; Gleason Grade; Gleason Grade for Prostate Cancer; Gleason Score; Gleason Score for Prostate Cancer; Gleason Sum; Gleason-SC; Goals; Grant; Group Identifications; Growth; health care personnel; Health Care Providers; health care worker; Health Personnel; health provider; healthcare personnel; Healthcare Providers; Healthcare worker; heavy metal lead; heavy metal Pb; ideation; Individual; Individual Differences; Intercept; Interdisciplinary Research; Interdisciplinary Study; Intervention; intervention design; Intervention Strategies; interventional strategy; Intestinal; Intestines; Investigation; Knowledge; Lack of Energy; Lead; Literature; Living Wills; Localized Disease; Malignant neoplasm of prostate; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant prostatic tumor; Malignant Tumor of the Prostate; man; man`s; Marital Status; Masks; Measures; medical personnel; Method LOINC Axis 6; Methodology; Methods; Methods and Techniques; Methods, Other; Modeling; Moods; Multidisciplinary Collaboration; Multidisciplinary Research; Multivariate Analyses; Multivariate Analysis; negative mood; ontogeny; Pain; Painful; Parents; pathophysiology; patient population; Patients; Pb element; Persons; Ph.D.; PhD; Physicians; Physiopathology; Principal Investigator; Process; programs; Programs (PT); Programs [Publication Type]; Prostate CA; Prostate Cancer; Prostatectomy; Prostatic Cancer; psychologic; psychological; Psychologist; Public Health; public health medicine (field); public health relevance; QOL; Quality of life; Recovery; Regrets; Research; research clinical testing; response; Review Literature; Risk; Sex Disorders; Sex Functioning; Sexual Dysfunction; sexual functioning; Shapes; side effect; social; Study, Interdisciplinary; SUBGP; Subgroup; Symptoms; Techniques; therapy adverse effect; therapy design; Thinking; Thinking, function; Time; Tissue Growth; treatment adverse effect; treatment design; Treatment outcome; treatment provider; Treatment Side Effects; urinary; Urologist; Variance Analyses
Project start date: 2008-05-01
Project end date: 2011-04-30
Budget start date: 1-MAY-2009
Budget end date: 30-APR-2011
PFA/PA: PA-06-351
5R21CA124786-02 (2009): $198210
INNATE IMMUNITY: ELUCIDATION AND MODULATION FOR CANCER THERAPY
A Michael
Ohio State Universitycity: Columbus country: United States (us)
Grant 5P01CA095426-10 from National Cancer Institute
Abstract: This Program Project Grant (PPG) competitive renewal application stresses innovative clinical cancer immunotherapy trials to a broad array of patients with hematopoietic and solid malignancies. There is also a strong, ongoing basic investigation among four highly integrated principal investigators focused entirely on human innate immune effector cell function in preparation for subsequent, more refined clinical cancer immunotherapy trials. Project 1 is focused on chronic lymphocytic leukemia (CLL) by targeting an alternative B-cell antigen, CD37, with a novel engineered small modular immune pharmaceutical (SMIP) that directly promotes apoptosis of CLL cells as well as SMIP-directed cell cytotoxicity. Project 1 uses the preclinical SCID-human chimeric mouse model of human B cell lymphoma to assess combination of the CD37-SMIP with a novel immune activator, IL-21, and will explore the direct and specific pro-apoptotic effect of IL-21 on CLL. Project 2 continues with elegant basic investigative work on Fc-gammaR signaling in human monocytes with broad application to natural killer (NK) and B cell biology as well as antibody dependent cellular cytotoxicity that is relevant to Projects 1, 3 and 4. Project 3 investigates the role of transforming growth factor-beta (TGF-beta) in dampening NK development and NK functions. These in vitro studies are complemented by two clinical trials assessing NK development and function in vivo while cancer patients with melanoma, renal cell carcinoma and pancreatic cancer will receive a "first in man" infusion of a humanized monoclonal antibody (mAb) that neutralizes TGF-beta. Project 3 will perform a clinical trial in patients with multiple myeloma infusing an antibody that recognizes a common epitope on inhibitory killer immunoglobulin like receptors (KIRs) in an effort to, 1) learn more about in vivo human NK development; 2) assess efficacy of NK killing against primary myeloma in the presence of KIR blockade; Project 4 utilizes both a preclinical murine model of breast cancer and a clinical trial in breast cancer to study the combination of IL-21 and trastuzumab (anti-HER2), while elucidating the signaling events behind synergy observed with IL-21 and Fc-gammaRllla activation in human NK cells. Collectively, in the first four years of progress, members of this P01 have accrued 248+ patients to clinical trials and have co-authored 75% of their 52 original, peer-reviewed publications. This work has broad application to cancer prevention and cure
Project start date: 2002-02-01
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5P01CA095426-10 (2011): $2012576
IDENTIFYING THE CORE BRAIN NETWORK DYSFUNCTION IN BIPOLAR DEPRESSION WITH FMRI
A Michael
University Of Cincinnaticity: Cincinnati country: United States (us)
Grant 5K23MH081214-04 from National Institute Of Mental Health
Abstract: This NIMH Mentored Patient-Oriented Career Development (K23) award application is to support Dr. Michael Cerullo´s long-term career objective of developing an expertise in the neurophysiology of depression in bipolar disorder (BPD) using innovative neuroimaging techniques. Little research has focused specifically on understanding the neurophysiology of depression associated with BPD, yet patients spend considerably more time in depressive rather than manic episodes and suffer more morbidity during depression. In order to achieve his career goals and advance our understanding of bipolar depression, the candidate proposes to gain expertise in functional MRI (fMRI), the neurophysiology of mood disorders, neuropsychology, statistical analysis, and the ethical conduct of research by participating in course work, didactic readings, mentoring, and the proposed research activities. By using fMRI and directly contrasting patients with major depressive disorder (MDD) and BPD during depression, it is possible to identify core brain regions involved in BPD. Only one prior fMRI study has directly compared BPD and MDD patients during depression, but was limited by the use of an exclusively emotional task. Bipolar patients, even while euthymic, also suffer cognitive deficits. The cognitive and mood symptoms of depression are generated by different but reciprocally connected brain networks and their interactions. Tasks that are purely emotional or cognitive may not permit examination of this interaction and may therefore be unable to elucidate brain abnormalities underlying mood dysregulation in BPD. Therefore we propose to use fMRI to compare regional brain activation between bipolar and unipolar depressed patients using a task designed to evaluate both the emotional and cognitive networks and their intersection. Prior neuroimaging research studies support the importance of the cerebellar vermis and striatum in BPD. We hypothesize that dysfunction in these two brain regions contributes to the breakdown in the regulation of the prefrontal-striatal-thalamic circuits that maintain emotional homeostasis. The proposed integrated research and training programs, together with the productive research environments of the Division of Bipolar Disorders Research and the Center for Imaging Research at the University of Cincinnati, will foster the candidate´s development into an independent investigator in mood disorders. The research conducted will advance our understanding of the neurophysiology of depression in BPD
Keywords: Address; Affect; Affective; Affective Disorders; Affective Psychosis, Bipolar; Anterior; Antidepressant Agent; Antidepressant Drugs; Antidepressants; Antidepressive Agents; Autoregulation; Behavior; bipolar affective disorder; Bipolar Depression; Bipolar Disorder; Brain; brain pathway; Brain region; career; career development; Cerebellar vermis structure; Clinical; Cognitive; Cognitive deficits; Cognitive Manifestations; Cognitive Symptoms; Complex; Corpus Striatum; Corpus striatum structure; cost; depressed; Depressed mood; Depression; depressive; depressive symptoms; design; designing; Development; Diagnosis; Disease; disease/disorder; Disorder; Dysfunction; Early treatment; effective therapy; Emotional; Emotional Depression; Encephalon; Encephalons; endophenotype; Environment; Ethical Analyses; Ethical Analysis; Evaluation; Exhibits; experiment; experimental research; experimental study; Face; facial; fatal attempt; fatal suicide; fMRI; Fostering; Functional disorder; Functional Imaging; Functional Magnetic Resonance Imaging; Generations; Goals; Health; heavy metal lead; heavy metal Pb; Homeostasis; Image; imaging; Individual; innovate; innovation; innovative; intent to die; Investigators; K23 Award; K23 Mechanism; K23 Program; Knowledge; Lead; Magnetic Resonance Imaging, Functional; major depression; Major Depressive Disorder; Manias; Manic; manic depressive disorder; manic depressive illness; Manic State; Measures; Mental Depression; Mentored Patient-Oriented Research Career Development Award; Mentored Patient-Oriented Research Career Development Award (K23); Mentors; Methods and Techniques; Methods, Other; Mind; Molecular; Mood Disorders; Moods; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; MRI, Functional; National Institute of Mental Health; National Institute of Mental Health (U.S.); Nervous System, Brain; network dysfunction; Neuranatomies; Neuranatomy; Neuroanatomies; Neuroanatomy; Neurobehavioral Manifestations; neuroimaging; neurophysiology; neuropsychologic; Neuropsychologies; Neuropsychology; NIMH; pathophysiology; patient centered; patient oriented; Patients; Pb element; Physiologic Imaging; Physiological Homeostasis; Physiopathology; Population; Prefrontal Cortex; prevent; preventing; programs; Programs (PT); Programs [Publication Type]; Psychosis, Manic-Depressive; Reading; recruit; Recruitment Activity; Recurrence; Recurrent; Regulation; Research; Research Activity; Research Ethics; Research Personnel; research study; Research Training; Researchers; response; sadness; Science of neurophysiology; Science of Statistics; self help organization; Self-Help Groups; Signs and Symptoms, Neurobehavioral; Source; statistics; Statistics; striatal; Striate Body; Striatum; suicidality; Suicide; Support Groups; Symptoms of depression; Techniques; Testing; thalamic; Thalamic structure; Thalamus; Time; Training Programs; trait; Translations; United States National Institute of Mental Health; Universities; Ventral Striatum; vermis; Vermis of Cerebelli; Work
Project start date: 2008-06-01
Project end date: 2013-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-05-143
5K23MH081214-04 (2011): $181332
5K23MH081214-03 (2010): $181332
DOPAMINE D2 RECEPTORS IN PRIMATE MODELS OF COCAINE ABUSE
A Michael, Professor
Wake Forest University Health Sciencescity: Winston-salem country: United States (us)
Grant 5R01DA012460-09 from National Institute On Drug Abuse
Abstract: This is an A1 submission of a competing renewal to continue research on the effects of novel dopamine D3 receptor compounds in rhesus monkey models of cocaine abuse. The D3 receptor is a subtype of the D2-like superfamily of receptors and because the relative expression of D3 receptors in the striatum is significantly less than that for D2 receptors, it has been hypothesize that preferential blockade of D3 receptors may lead to selective antagonism of the reinforcing and discriminative stimulus effects of cocaine without producing motor side- effects. Specific Aim 1 will utilize several animal models to evaluate the in vivo agonist efficacy of D3 compounds and to determine the potency, efficacy and time course of behavioral effects. With this information, compounds will be evaluated in drug discrimination and drug self- administration models of cocaine (Specific Aim 2) and methamphetamine (MA) (Specific Aim 3) abuse. We hypothesize that partial agonists with the highest D3 affinity will show agonist-like effects on unconditioned behaviors such as drug-induced yawning and locomotor activity. We also hypothesize that full agonists and D3 partial agonists will substitute for the partial agonist CJB 090 in drug discrimination studies, while D3 antagonists will not substitute. In models of drug abuse, we hypothesize that D3-selective partial agonists and antagonists will attenuate the discriminative stimulus effects of cocaine and MA, with an order of potency directly related to their selectivity at D3 vs. D2 receptors. In self-administration studies using a concurrent food- drug schedule, we hypothesize that D3 compounds will decrease drug choice (both cocaine and methamphetamine) and shift preference to food reinforcement, while non-selective D2-like compounds will decrease overall behavior. Finally, we hypothesize that D3-selective compounds will be effective at attenuating cocaine- and MA-induced reinstatement under the concurrent schedule. These studies should add valuable information about in vivo pharmacology related to D3 compounds, as well as how these drugs affect multiple behavioral endpoints related to cocaine and MA abuse. Such knowledge will aid in the development of effective pharmacotherapies for stimulant abuse. The dopamine D3 receptor has been identified as a novel and important target for pharmacotherapies combating drug addiction. These studies will utilize several compounds with some of the greatest selectivity for this receptor subtype in an effort to better understand how dopamine D3 receptors mediate the high abuse liability of cocaine and methamphetamine using nonhuman primate models
Keywords: Adverse effects; Affect; Affinity; Agonist; Animal Model; Animals; Area; Attenuated; Behavior; Behavioral; Binding (Molecular Function); Biological Assay; Body Temperature; Brain; Brain region; Cocaine; Cocaine Abuse; cocaine overdose; combat; comparative efficacy; Corpus striatum structure; D3 compound; density; design; Development; Discrimination (Psychology); Dopamine; Dopamine Agonists; Dopamine D2 Receptor; dopamine D3 receptor; Dopamine Receptor; Dose; Drug abuse; Drug Addiction; drug discrimination; drug induced behavior; drug of abuse; drug testing; Food; Funding; Goals; Grant; Health; Human; In Vitro; in vivo; Islands of Calleja; Knowledge; Lead; Macaca mulatta; Mediating; Methamphetamine; methamphetamine abuse; Modeling; Monkeys; Motor; Motor Activity; nonhuman primate; novel; Nucleus Accumbens; Olfactory tubercle; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiologic Thermoregulation; preference; Primates; Psychological reinforcement; Psychostimulant dependence; Quinpirole; receptor; reinforcer; Relative (related person); Research; Role; Schedule; Self Administration; Series; stimulant abuse; Stimulus; Testing; therapeutic target; Time; Training; Work; Yawning
Project start date: 2000-09-30
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01DA012460-09 (2011): $341512
VASCULAR, PULMONARY AND RENAL INJURY
A Michael, Professor And Chairman
Brigham And Women´s Hospitalcity: Boston country: United States (us)
Grant 5T32HL007627-27 from National Heart, Lung, And Blood Institute
Abstract: This Competing Continuation Application for a well-established Ruth L. Kirschstein Institutional National Research Service Award (T32) is focused on the postdoctoral training of M.D., M.D.-Ph.D., and Ph.D. candidates to prepare them to pursue independent careers as successful Clinician-Scientists and/or Biomedical Research Scientists, whose primary interest is the cellular and molecular mechanisms of human disease. Its primary training goal is the development of core research competencies through both informal and structured didactic exercises, coupled with an in-depth mentored research experience, in a nurturing and supportive academic medical center environment. The programmatic emphasis is on understanding the basic pathogenetic mechanisms underlying major disease processes that affect the cardiovascular, pulmonary, hematopoietic and immune systems, through the application of the multidisciplinary research tools and strategies of modern cellular and molecular biology, immunology, genetics and genomics, integrative physiology and bioinformatics. The current Training Program, sponsored by the National Heart, Lung and Blood Institute, has been in continuous existence since 1958, and is based in the Department of Pathology at the Brigham and Women´s Hospital, a primary teaching affiliate of Harvard Medical School. While the Training Program´s Core Faculty is comprised primarily of clinician-scientists and basic biomedical researchers in the Department of Pathology, trainees also are encouraged to avail themselves of a wide spectrum of opportunities afforded by research mentors/laboratories in Harvard-affiliated research/medical center institutions (e.g., The Immune Diseases Institute - formerly the Center for Blood Research, the Broad Institute, Children´s Hospital Boston, Massachusetts General Hospital, Massachusetts Institute of Technology and Dana-Farber Cancer Institute). Trainees are selected from a national pool of applicants, via a proactive recruitment process, and the Program´s emphasis is on tailoring a research training experience to fit a given candidate´s background, scientific interests and career goals. The overarching scientific principle is one of translational molecular pathology - the probing of disease mechanisms at a fundamental mechanistic level that yields new insights that point the way to targeted treatments for diseases, and, ultimately, their prevention. RELEVANCE (See instructions) Diseases of the cardiovascular system (e.g., heart attacks and strokes), as well as disorders of the blood and immune systems (e.g., autoimmune disorders) represent a major health burden. Equipped with the skills of modern molecular pathology, new researchers can learn to probe the basic mechanisms of these diverse diseases and then translate this knowledge into novel and effective treatments and preventative measures
Keywords: Blood Vessels; Injury; Kidney; Lung
Project start date: 1985-07-01
Project end date: 2015-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-08-226
5T32HL007627-27 (2011): $642777
2T32HL007627-26 (2010): $706035
Sponsored Links Excellgen http://Excellgen.com
IN VITRO AND IN VIVO LUNG STUDIES
A Michael, Professor
University Of California San Franciscocity: San Francisco country: United States (us)
Abstract: This Cell Culture and Animal Core is designed to support specific aims in each of the 4 projects in this revised Program Project Application. There are two specific aims. The first aim is to supply alveolar epithelial type II cells from human lungs, rat lungs, and mouse lungs to support the specific aims of Project 1 (Mostov), Project 2 (Engel), and Project 3 (Rosen). Our research group has had extensive experience in isolating, culturing, and studying pulmonary alveolar epithelial type II cells from human and rodent lungs under both normal and pathological conditions. This work has been especially productive in studying mechanisms of alveolar epithelial injury from P.aeruginosa ExoT and ExoS as well as establishing how the ADP ribosyl transferase domain of P.aeruginosa ExoT contributes to the biologic activities of the Pseudomonas organisms (Project 2, Engel). In addition, our recent work has established that human alveolar epithelial type II cells can be cultured in matrigel and induced to form 3-dimentional structures that resemble authentic alveolar-like structures. This accomplishment provides a major opportunity for novel studies of lung epithelial function under normal and pathologic conditions (Project 1, Mostov). The second aim of this core, which represents an expanded direction, is to carry out in vivo mouse studies using pathologic models of lung injury to test specific hypotheses in Project 3 (Rosen) and Project 4 (Werb). These in vivo mouse experiments will use both infectious and non-infectious stimuli to test the effects on lung function and overall survival. Our research group has extensive experience with in vivo studies and there is considerable preliminary data that has been generated in testing specific hypotheses that a part of Project 3 (Rosen) and Project 4 (Werb)
Keywords: Acids; Alveolar; Animals; Cell Culture Techniques; Data; design; Epithelial; Epithelial Cells; experience; Human; Immune; Immunity; In Vitro; in vivo; Infection; Injury; Lung; lung injury; matrigel; Modeling; Mus; novel; Organism; Pathologic; programs; Pseudomonas; Pseudomonas aeruginosa; Rattus; Research; research study; Respiratory physiology; Rodent; Stimulus; Structure; Testing; Transferase; Type II Epithelial Receptor Cell; Work
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5P01AI053194-09_9004 (2011): $146246
STUDIES ON THE POST-TRANSLATIONAL PROCESSING OF MUC1
A Michael, Professor
University Of Nebraska Medical Centercity: Omaha country: United States (us)
Grant 5R01CA057362-16 from National Cancer Institute
Abstract: This application proposes experiments that will further explore the molecular mechanisms by which the cell surface associated mucin, MUC1, contributes to the progression of pancreatic adenocarcinoma. Previous work has established that MUC1 is overexpressed and differentially glycosylated by different adenocarcinomas, and that this overexpression is associated with aggressive (invasive and metastatic) forms of pancreatic and other cancers. MUC1 plays multiple and key roles at the cell surface of epithelial cells it configures some aspects of cell surface adhesion properties, and it communicates information about the status of the cell surface to the nucleus through participation in different pathways of signal transduction. We now know that alterations in MUC1 structure or binding status are communicated to internal compartments of the cell through modifications of the cytoplasmic tail, which can be phosphorylated by different serine, threonine and tyrosine kinases. Our recent results have revealed that MUC1 can have dramatic modulatory effects on cellular functions in response to external growth factor/cytokine stimulation through interactions with receptor tyrosine kinases. MUC1 overexpression on pancreatic tumor cells significantly increases the invasive and metastatic properties of cells stimulated with PDGF-BB. The mechanism whereby this occurs involves phosphorylation of the MUC1 cytoplasmic tail by PDGFR2 and subsequent signaling by the MUC1 cytoplasmic tail, which is transported to and modifies the transcriptional activity of specific promoter sites in the nucleus in association with other signaling and transcription factors. In contrast to the results with PDGF-BB, stimulation of pancreatic tumor cells with hepatocyte growth factor (HGF) under conditions of MUC1 overexpression decreases cell invasive through a mechanism in which MUC1 cytoplasmic tail phosphorylated by cMet associates with p53 and modulates the ability of p53 to associate with AP-1 at promoter sites and activate expression of genes associated with invasion (e.g. MMP1). These results support previous findings that MUC1 can influence the invasive and metastatic properties of tumors in different ways (both enhancing and decreasing). Our results provide a molecular explanation for these different effects by showing that they are context dependent and affected by the cytokine and tissue environment of the cell on which MUC1 is expressed. These results provide new insight into the overall metastatic process, in which cells first take on activities of invasion to leave a primary tumor site, which can be shut down when metastatic tumor cells take up residence in a new organ site and no longer need to migrate. As we go forward we have chosen to focus this renewal application on the mechanisms by which MUC1 is involved in signal transduction and transcriptional regulation, and how this influences invasion and metastasis of pancreatic tumor cells. This application proposes experiments that will further explore the molecular mechanisms by which the cell surface associated mucin, MUC1, contributes to the progression of pancreatic adenocarcinoma. This renewal application will investigate the mechanisms by which MUC1 is involved in signal transduction and transcriptional regulation, and how this influences invasion and metastasis of pancreatic tumor cells
Keywords: Adenocarcinoma; Adhesions; Adhesives; Affect; Apical; Area; Autologous; beta catenin; Binding (Molecular Function); Biological; Cell Adhesion Molecules; Cell Communication; cell motility; Cell Nucleus; Cell physiology; Cell Polarity; Cell surface; cell transformation; Cells; Chromatin; Cleaved cell; Complex; cytokine; Cytoplasmic Tail; Environment; Epithelial Cells; Estrogen Receptors; Event; extracellular; Extracellular Domain; Extracellular Matrix; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Grant; Growth Factor; Health; Hepatocyte Growth Factor; insight; Integrins; Interstitial Collagenase; Knowledge; Laboratories; Lateral; Lectin; Left; Ligands; Literature; Malignant Neoplasms; Mediator of activation protein; meetings; metastatic process; MMP1 gene; Modification; Molecular; Mucin-1 Staining Method; Mucins; Nature; Neoplasm Metastasis; neoplastic cell; Organ; Outcome; overexpression; Pancreas; Pancreatic Adenocarcinoma; pancreatic neoplasm; PDGFRA gene; Phosphorylation; Phosphotransferases; platelet-derived growth factor BB; Play; Primary Neoplasm; Process; Promotor (Genetics); Property; protein function; Protein Tyrosine Kinase; Protein-Serine-Threonine Kinases; Proteins; receptor; Receptor Protein-Tyrosine Kinases; research study; residence; response; Role; sensor; Serine; Signal Transduction; Signal Transduction Pathway; Site; Structure; Surface; Surface Properties; Tandem Repeat Sequences; Threonine; Tissues; TP53 gene; transcription factor; Transcription Factor AP-1; Transcriptional Regulation; tumor; Tumor Cell Invasion; Tyrosine; Work
Project start date: 1992-09-01
Project end date: 2013-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01CA057362-16 (2011): $236859
PHASE I CLINICAL TRIALS OF NEW ANTI-CANCER TARGETED THERAPIES
A Michael, Associate Professor
Johns Hopkins Universitycity: Baltimore country: United States (us)
Grant 5U01CA070095-17 from National Cancer Institute
Abstract: This application is to evaluate promising new therapies for patients with malignant disease in a clinically efficient, regulatory-compliant, and scientifically rigorous research environment. Phase I clinical studies of new anti-cancer therapies continue to evolve as basic / translational research has broadened the targeted opportunities to treat malignant disease. Building upon a strong foundation in the conduct of phase I studies, we have assembled an interactive research team that uses rationally designed clinical trials that enhances the molecular / pharmacologic assessment of new drug activity. These trials and assessment methods are designed ultimately to impact on the clinical care of patients diagnosed with cancer. The overall objective of these Phase l/ll studies is to determine the appropriate dose and schedule of experimental agents for further evaluation of efficacy in solid tumor /hematologic malignancies and to characterize the acute and chronic toxicities of these anti-cancer therapies. Our Specific Aims are 1) To conduct Phase I clinical trials of novel anti-cancer agents (alone or in combination) in a timely manner; 2) To perform detailed pharmacokinetic studies of these new agents and to correlate these observations with relevant clinical I biologically sound endpoints; 3) To implement correlative and pharmacodynamic laboratory evaluations in proof of drug mechanism phase I clinical trials and to explore optimal relationships between parameters of drug exposure and biological effects; and 4) To maintain a clinical trial infrastructure that is current and compliant with regulatory standards that assure quality care to patients enrolled on early phase clinical trials. Over the past 4 years, our UO1 Phase I program has enrolled over 500 patients (131 patients/year average), completed 12 trials, submitted 38 Letters of Intent, have 12 ongoing trials and 4 new trials approved, and have over 80 publications directly related to this Collaborative agreement. Our research group remains flexible to expansion and to explore other targets of interest / trial designs as well as well-positioned to further incorporate novel imaging into our early phase clinical trials. Given our productivity, experience, and expertise in early phase clinical trials, we fully expect to enroll 100 patients / year and to complete 2-3 phase l/ll clinical trials/ year via this cooperative agreement. Scientifically, members of our program will continue active participation in the Investigational Drug Steering Committee (IDSC)
Keywords: Acute; Agreement; Anti-Cancer Agents; Anti-Tumor Agents; Anti-Tumor Drugs; anticancer agent; anticancer drug; anticancer therapy; Antineoplastic Agents; Antineoplastic Drugs; Antineoplastics; Antiproliferative Agents; Antiproliferative Drugs; Biological; Cancer Drug; cancer therapy; Cancer Treatment; Cancers; Chemotherapeutic Agents, Neoplastic Disease; Chronic; Clinical; clinical care; clinical investigation; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials Design; Clinical Trials, Phase I; Clinical Trials, Unspecified; Cooperative Agreements; Cooperative Agreements, U-Series; design; designing; Diagnosis; Disease; disease/disorder; Disorder; Dose; Drug Exposure; Drug Kinetics; drug mechanism; drug/agent; Drugs; Drugs, Investigational; Early-Stage Clinical Trials; efficacy evaluation; enroll; Enrollment; Environment; Evaluation; experience; flexibility; Foundations; Hematologic Cancer; Hematologic Malignancies; Hematologic Neoplasms; Hematological Malignancies; Hematological Neoplasms; Hematological Tumor; Hematopoietic Cancer; Image; imaging; Infrastructure; interest; Investigational Drugs; Investigational New Drugs; Laboratories; Letters; malignancy; Malignant; Malignant - descriptor; Malignant Hematologic Neoplasm; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; Medication; member; Methods; Molecular; neoplasm/cancer; New Agents; novel; Patients; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Pharmacokinetics; Phase; Phase 1 Clinical Trials; phase 1 study; phase 1 trial; Phase I Clinical Trials; Phase I Study; phase I trial; Position; Positioning Attribute; Productivity; programs; Programs (PT); Programs [Publication Type]; protocol, phase I; Publications; QOC; Quality of Care; Research; Research Infrastructure; SCHED; Schedule; Scientific Publication; Solid Neoplasm; Solid Tumor; sound; Sound; Sound - physical agent; Toxic effect; Toxicities; translation research enterprise; Translational Research; Translational Research Enterprise; Translational Science; Tumor-Specific Treatment Agents; U-Series Cooperative Agreements
Project start date: 1995-09-22
Project end date: 2013-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: RFA-CA-07-031
5U01CA070095-17 (2011): $793299
5U01CA070095-16 (2010): $881441
FUNCTIONAL CHARACTERIZATION OF MLL GENE FUSIONS
A Michael
Ohio State Universitycity: Columbus country: United States (us)
Grant 5R01CA089341-08 from National Cancer Institute
Abstract: This application is for renewal of our NCI-funded R01 grant entitled "Functional Characterization of MLL Gene Fusions" (last score17.2 percentile). The central hypothesis of our work is that the MLL Partial Tandem Duplication (PTD) represents a primary molecular defect in myeloid hematopoietic progenitor cells that is responsible, at least in part, for leukemic transformation, and will prove to be a valuable target for therapeutic intervention in MLL PTD acute myeloid leukemia (AML) patients who have a poor prognosis. Our overall goal is to elucidate molecular mechanisms underlying this subset of AML such that we will have the greatest impact on increasing cure rate of this disease by molecular-based risk stratification and targeted therapeutics. During the previous funding period, our early success in generating the heterozygous Mll ptd knock-in mouse allowed us to begin our efforts 1) examining hematopoiesis and downstream Mll targets in vitro and in vivo- we found proliferative and self-renewal abnormalities in hematopoietic progenitors but no frank leukemia; 2) characterizing the first overt phenotype observed- skeletal deformities associated with aberrant HoxA gene expression and 3) elucidating the novel epigenetic mechanism responsible for HoxA gene deregulation in Mllptd/wt mice. We also carried out genome-wide profiling in human MLL PTD AML and have gained considerable insight into MLL PTD-associated pathways. Indeed, we demonstrated primary MLL PTD AML blasts express the MLL self-fusion but silence the MLL wild-type allele. The latter can be reversed by pharmacological inhibitors of DNA methyltransferase and histone deacetylase and also by direct targeting of the MLL PTD using anti-sense oligodeoxynucleotides. Both approaches resulted in enhanced apoptosis of these leukemic blasts in vitro. During the next funding cycle, we will extend these findings through the following aims 1) further characterize the Mll ptd to best understand how this mutation impacts the genesis and propagation of AML; 2) elucidate cooperating events that together with the Mll ptd give rise to AML. Indeed, we recently generated an Mll ptd/Flt3 itd double mutant mouse model, and 100% of these mice develop aggressive acute leukemia. Initial full phenotypic analyses in two mice reveal AML or undifferentiated stem cell acute leukemia. These mice will be used to carry out hypothesis-driven research as outlined and will be useful for assessing novel targeted therapeutics. Collectively, we believe this work will reveal insights as to how to best treat MLL PTD AML patients. Collectively, we believe this work will reveal insights as to how to best treat patients with Acute Myelogenous Leukemia and the Partial Tandem Duplication of the Mixed Lineage Leukemia Gene
Keywords: Acute; acute granulocytic leukemia; Acute leukemia; acute myeloid leukemia; acute nonlymphocytic leukemia; Address; Affect; ALL1; Alleles; Allelomorphs; AML - Acute Myeloid Leukemia; Anaplastic; Anatomic Abnormality; Anatomical Abnormality; Apoptosis; Apoptosis Pathway; base; Biological Models; Biology; Blast Cell; Blasts; Blood (Leukemia); Blood Precursor Cell; Cell Death, Programmed; cell growth; Cell Survival; Cell Viability; Cells; Cellular Expansion; Cellular Growth; Clinical; Congenital or Acquired Anatomic Abnormality; Congenital or Acquired Anatomical Abnormality; Data; Defect; Deformity; Development; DNA Methylation; DNA Methyltransferase Inhibitor; Epigenetic; Epigenetic Change; Epigenetic Mechanism; Epigenetic Process; Evaluation; Event; Ferrata cell; Forecast of outcome; Funding; Gene Deregulation; Gene Expression; Gene Fusion; Genetic Alteration; Genetic Change; Genetic Condition; Genetic defect; Genetic Diseases; genetic disorder; genome mutation; genome-wide; Goals; Grant; HDAC; HDAC Proteins; Health; heavy metal lead; heavy metal Pb; Hematohistioblast; Hematopoiesis; Hematopoietic; Hematopoietic Cellular Control Mechanisms; Hematopoietic stem cells; Hemocytoblast; Hemohistioblast; Hereditary Disease; hereditary disorder; Histone Deacetylase; HRX; HTRX; Human; Human, General; In Vitro; in vivo; in vivo Model; insight; intervention therapy; Knock-in; Knock-in Mouse; Laboratories; Lead; LEUKCL; leukemia; Leukemia, Myelocytic, Acute; Leukemias, General; Leukemic Cell; leukemogenesis; Leukemogenesis/Lymphomagenesis; Mammals, Mice; Man (Taxonomy); Man, Modern; Manuscripts; Mice; Micro RNA; MicroRNAs; miRNA; Mixed Lineage Leukemia Gene; MLL; MLL gene; Model System; Models, Biologic; Molecular; Molecular Disease; Mother Cells; mouse model; Murine; Mus; mutant; mutant mouse model; Mutation; Myeloblastic Leukemia, Acute; Myelogenous; Myelogenous Leukemia, Acute; Myeloid; Myeloid-Lymphoid Leukemia Gene; new therapeutic target; new therapeutics; next generation therapeutics; novel; novel therapeutics; Oncogene Deregulation; outcome forecast; pathway; Pathway interactions; Patients; Pattern; Pb element; Phenotype; progenitor; Progenitor Cells; Progenitor Cells, Hematopoietic; Prognosis; Publishing; Research; response; Risk; self-renewal; skeletal; Stem cells; Stratification; success; Therapeutic Intervention; therapeutic target; TRX1; Undifferentiated; Work
Relevance: Collectively, we believe this work will reveal insights as to how to best treat patients with Acute Myelogenous Leukemia and the Partial Tandem Duplication of the Mixed Lineage Leukemia Gene
Project start date: 2000-12-01
Project end date: 2013-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PA-07-070
5R01CA089341-08 (2011): $257987
3R01CA089341-08S1 (2011): $15769
SPORE IN GASTROINTESTINAL CANCER
A Michael, Professor
University Of Nebraska Medical Centercity: Omaha country: United States (us)
Grant 5P50CA127297-04 from National Cancer Institute
Abstract: This application for a Specialized Program of Research Excellence in Gastrointestinal (Pancreatic Cancer) will focus on translational studies that address basic and clinical issues of importance to improving the outcome of patients with pancreatic cancer. Specifically, the research projects in this program seek to 1) develop and test novel diagnostic reagents and assays that will improve our ability to detect pancreatic cancer in its early stages; 2) develop and test novel therapeutic strategies including immunotherapy, chemotherapy, and chemoradiation therapy for patients with early and advanced pancreatic cancer; 3) undertake basic research studies in conjunction with clinical trials that will provide insight at the molecular level into the reasons for success and failure of the different strategies. The proposed SPORE program is focused on 4 projects with the high potential translational impact, and there are 2 highly interactive cores that will continue to acquire, store, and make available a unique set of tissue samples, data (clinical, molecular genetic, biological, pathological), reagents and resources Project 1 Immunotherapy of Pancreatic Adenocarcinoma Project 2 Inhibitors of N-cadherin in the treatment of pancreatic cancer. Project 3 Biological marker(s) in the diagnosis of pancreatic cancer Project 4 Inhibitors of Telomerase in treatment of pancreatic adenocarcinoma Core 1 Administration Core 2 Pancreas Tumor SPORE Tissue Bank Core 3 Biostatistics
Project start date: 2008-09-05
Project end date: 2013-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PAR-06-505
5P50CA127297-04 (2011): $1013333
GENOMIC AND GENETIC STUDIES OF DIABETIC RETINOPATHY
A Michael, Asst Prof Of Clinical Ophthalm
University Of Illinois At Chicagocity: Chicago country: United States (us)
Grant 5K08EY019089-05 from National Eye Institute
Abstract: There have been extensive research efforts for more than a decade to understand the genetics of diabetic retinopathy. To date, linkage and candidate gene associations have failed to deliver definitive results. Despite this challenge, it is well accepted that the identification of genetic variants, thereby implicating genes and pathways involved in the pathogenesis of diabetic retinopathy, offers an important mechanism by which to generate new therapies and better prevent this disease. With the completion of the human genome project, as well as the HapMap project, and the availability of platforms like the Affymetrix 500k SNP chip combined with bioinformatic computational methods, it is now possible to identify genetic variants on a genome scale in a cost effective manner. The major limiting factor remains accessing large, well phenotypically characterized cohorts of patients. To this end, we have established collaborations to analyze two large populations of patients with retinopathy due to type 1 diabetes. Specific Aim 1. To carry out a genome wide association study of SNPs in a cohort of type 1 diabetic subjects with severe eye disease and controls ascertained from the Genetics of Kidneys in Diabetes (GoKinD) study to map genes associated with diabetic retinopathy. Specific Aim 2. To confirm significant findings from this genome wide association in a separate cohort of type 1 diabetic individuals with severe eye disease and controls ascertained from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). Specific Aim 3. To carry out fine-mapping studies in genes or regions showing association with diabetic retinopathy and perform detailed genotype-phenotype analyses. The relevance of this research to public health is that an understanding of the genetic basis of diabetic retinopathy should lead to novel treatments and methods for preventing this diabetic complication
Keywords: Adult; Age; Americas; base; Bioinformatics; Blindness; Candidate Disease Gene; Chromosome Mapping; cohort; Collaborations; Complications of Diabetes Mellitus; Computing Methodologies; cost effective; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; disorder control; Epidemiologic Studies; Eye diseases; Genes; Genetic; genetic variant; Genome; genome wide association study; Genomics; Genotype; Human Genome Project; Individual; Insulin-Dependent Diabetes Mellitus; Kidney; Knowledge; Lead; Maps; Methods; novel; Pathogenesis; Pathway interactions; patient population; Patients; Phenotype; prevent; Prevention; public health medicine (field); Research; Retinal Diseases; Risk; Single Nucleotide Polymorphism; type I diabetic; Variation (Genetics); Vision; Wisconsin; Work
Project start date: 2008-09-15
Project end date: 2013-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-06-512
5K08EY019089-05 (2011): $225634
7K08EY019089-04 (2010): $192873
EFFECTS OF CHRONIC TREATMENT WITH PUTATIVE PHARMACOTHERAPIES ON THE REINFORCING A
A Michael, Professor
Wake Forest University Health Sciencescity: Winston-salem country: United States (us)
Abstract: There are currently no FDA-approved medications for cocaine addiction. In the previous funding period, several animal models of cocaine abuse were used by this Center to investigate the neuropharmacology of chronic cocaine exposure. The studies described in Project 1 combine three research areas that were separated into distinct Projects in the previous version of the Center (formerly Projects 3, 5 and 6). These studies are designed to systematically investigate in monkeys and rats current medications used clinically to beat cocaine addiction, as well as drugs in the clinical "pipeline" and drugs that are not approved for human use, but could provide information related to mechanisms of action related to clinical efficacy. Specific Aim 1 will use rhesus monkeys self-administering cocaine to examine the effects of chronic administration of drugs. Treatment drugs that selective decrease cocaine- relative to food-reinforced responding, with no evidence of tolerance or attenuation by higher cocaine doses, will be evaluated in monkey models of cognition (Specific Aim 2). A positive outcome in models of cognition (i.e., improvement in performance) will yield additional studies in experimentally naive monkeys in combination with imaging studies (Projects 2 and 3). Finally, Specific Aim 3 will examine the effects of acute and chronic administration of drug treatments in several rat models of cocaine self-administration. When complete, the studies in this Project will provide basic science information in monkeys and rats across several behavioral endpoints in which different aspects of addiction are modeled, which should be of relevance to clinicians
Keywords: Abstinence; Acute; addiction; Affect; Animal Model; Animals; Area; attenuation; base; Basic Science; Behavioral; Brain imaging; brain tissue; Chronic; Clinical; clinical efficacy; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Dependences; cocaine exposure; Cognition; Cognitive; cognitive function; Data; design; Development; Dose; Drug effect disorder; drug of abuse; Drug usage; effective therapy; extracellular; FDA approved; Food; Funding; Future; gamma-Aminobutyric Acid; Goals; Human; Image; In Vitro; in vivo; Lead; Macaca mulatta; Measures; Mediating; Modeling; Monkeys; Neurobiology; neurochemistry; Neuropharmacology; Neurotransmitters; novel; Outcome; Performance; Pharmaceutical Preparations; Pharmacotherapy; Positron-Emission Tomography; prevent; Procedures; Psychological reinforcement; Rattus; Recording of previous events; Reinforcement Schedule; Relative (related person); Research; Research Design; Research Personnel; Rodent; Sampling; Schedule; Self Administration; Self-Administered; Serotonin; Signal Transduction; System; Testing; Tissues; Training; treatment effect; Treatment Effectiveness; treatment strategy; Work
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
5P50DA006634-20_8745 (2011): $614640
Sponsored Links Excellgen http://Excellgen.com
SIMULTANEOUS ANALYSIS OF NEUROCHEMICAL AND BEHAVIORAL/COGNITIVE EVENTS IN VIVO
A Michael, Assistant Professor
University Of Kansas Lawrencecity: Lawrence country: United States (us)
Grant 5R21NS070263-02 from National Institute Of Neurological Disorders And Stroke
Abstract: The use of fast scan cyclic voltammetry (FSCV) in conjunction with discrete behavioral events, such as learned lever presses, has proven to be a useful approach for studies of addiction and reward-based learning. Nevertheless, it neglects behavioral events that occur between lever presses and is limited in that the occurrence of many behaviors may not be identifiable by unaided human observation, placing a fundamental limitation on how much neurochemical information can be attributed to behaviors. Therefore, there is a critical need to develop an approach capable of correlating subtle movement with neurochemical measurements. The long-term goal is to develop methods that facilitate researchers´ efforts to understand brain function. The central aim of this proposal is to advance the ability of laboratory scientists to correlate brain DA transients with ongoing behavior by combining FSCV with high-resolution behavioral methods. The rationale is that integration of FSCV with the force-plate actometer, which is capable of objectively measuring subtle rodent movements on temporally compatible timescales, will empower investigators to combine FSCV measurement with more complex, and more informative, behavioral assays. To facilitate the use of this integrated approach for complex cognitive/behavioral paradigms, a hybrid operant chamber with a force-plate actometer as its floor will be used to study the differential reinforcement of low rates behavioral paradigm while collecting FSCV data. Because the proposed methods will help bridge the gap between motor and cognitive function and neurochemistry, it will have broad applicability to many areas of research including, but not limited to (1) fundamental neurobiological studies of dopamine signaling and behavior/cognition; (2) dopamine-related movement disorders [e.g. Huntington´s disease (HD), Parkinson´s disease (PD), Tourette´s syndrome (TS)]; (3) studies of addiction and compulsion; and (4) mechanisms of action of CNS-active pharmacological agents. Thus, the proposed research is relevant to that part of NIH´s mission pertaining to the development of fundamental knowledge that will potentially help reduce the burdens of human illness and disability. The central aim will be accomplished by completion of the following two specific aims (1) Apply a combined behavioral/voltammetric paradigm for monitoring sub-second behaviors and corresponding neurochemical changes associated with reward expectation and delivery and (2) Apply the combined behavioral/voltammetric methodology to measure dopamine transients associated with self-initiated behaviors. This combined, high time resolution approach is innovative because it is the first approach to make use of simultaneous high temporal resolution neurochemical and behavioral measurements in a complex cognitive task. The proposed research is significant because it will expand the ability of neuroscientists to correlate brain dopamine system functions with learned, motivated rodent behaviors and thereby provide new information fundamental to understanding a range of health problems in which dopamine plays a role. The proposed studies are designed to enhance the ability of investigators to conduct in vivo experiments aimed at resolving how sub-second alterations in extracellular dopamine levels impact subtle and complex cognitive behaviors. The proposed research has relevance to public health because this approach can be applied towards unraveling the underlying mechanisms associated with dopamine-related neurological disorders
Keywords: addiction; Addictive Behavior; Address; Area; awake; base; Behavior; behavior measurement; Behavioral; Behavioral Assay; Behavioral Paradigm; Brain; carbon fiber; Cognition; Cognitive; cognitive function; Complex; Corpus striatum structure; Data; Decision Making; design; Development; disability; Dopamine; dopamine system; Electrodes; empowered; Environment; Event; expectation; extracellular; Floor; Flowers; Gilles de la Tourette syndrome; Goals; Health; Human; Huntington Disease; Hybrids; Impaired cognition; in vivo; Ingestion; innovation; insight; instrument; Investigation; Knowledge; Laboratory Scientists; Learning; Legal patent; Measurement; Measures; Mental Depression; Methodology; Methods; Mission; Monitor; Motor; Movement; Movement Disorders; neglect; nervous system disorder; Neurobiology; neurochemistry; Neurodegenerative Disorders; Neurologic; Neuromodulator; Neurosciences; Neurotransmitters; novel strategies; Nucleus Accumbens; Obsessive-Compulsive Disorder; Parkinson Disease; Play; Procedures; programs; Psychological reinforcement; public health medicine (field); public health relevance; Rattus; Research; Research Design; Research Personnel; research study; Resolution; response; Rewards; Rodent; Role; Scanning; sequence learning; Signal Transduction; Societies; Techniques; theories; Time; Training; Uncertainty; uptake; Work
Relevance: The proposed studies are designed to enhance the ability of investigators to conduct in vivo experiments aimed at resolving how sub-second alterations in extracellular dopamine levels impact subtle and complex cognitive behaviors. The proposed research has relevance to public health because this approach can be applied towards unraveling the underlying mechanisms associated with dopamine-related neurological disorders
Project start date: 2010-04-01
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-09-164
5R21NS070263-02 (2011): $162250
IDENTIFICATION OF NOVEL THERAPEUTIC APPROACHES FOR TETS AND OP INTOXICATION
A Michael, Assoc Prof Of Neurotoxicology
University Of California Daviscity: Davis country: United States (us)
Grant 5R21NS072094-02 from Office Of The Director, National Institutes Of Health
Abstract: The rodenticide tetramethylenedisulfotetramine (TETS) and the organophosphorus (OP) pesticide parathion are considered credible terrorist threat agents. Current medical countermeasures for acute TETS or OP intoxication can prevent mortality but do not sufficiently protect the CNS from persistent seizures and/or permanent injury. Therefore, new and more effective countermeasures must be developed to facilitate better medical treatment of civilians, first responders and military personnel following exposure to acutely toxic levels of TETS, parathion and similar chemical threat agents. The goals of the proposed research are to develop rodent models of TETS- and parathion-induced seizures and then use these models to identify potential therapeutic agents. We seek to identify agents that can protect against the development of seizures or treat seizures once they have begun and/or can prevent irreversible neuronal injury. We plan to evaluate a 2,3- benzodiazepine AMPA receptor antagonist and a soluble epoxide hydrolase inhibitor (sEHi). We have recently shown that AMPA receptor antagonists provide sustained seizure protection and are able to block seizures when administered at later times when there is refractoriness to diazepam, the benzodiazepine typically used to treat acute TETS and OP intoxication. We and others have data indicating that sEHi also exhibit anti- epileptic properties. Perhaps more important in light of recent evidence suggesting that the use of anti- inflammatory compounds in combination with standard antidote significantly decreases neuronal damage in acute OP intoxication, we have demonstrated that sEHi are also potent anti-inflammatory compounds. These observations suggest the potential for AMPA receptor antagonists and sEHi to significantly improve the clinical management of acute TETS and parathion intoxication by extending the therapeutic window and enhancing neuroprotection. To test this hypothesis, we will address two specific aims (1) Develop rodent models of acute TETS and parathion intoxication; and 2) Determine whether AMPA receptor antagonist and/or sEHi are of therapeutic benefit in acute TETS or parathion intoxication when administered prior to or after exposure to the chemical threat agent. Endpoints that will be measured across all Aims include time to onset, frequency and duration of clonic and tonic seizures, EEG, histological measures of neuropathology and blood levels of TETS, AMPA receptor antagonist and sEHi. AMPA receptor antagonists and sEHi are currently undergoing human clinical trials and have demonstrated an excellent safety record; which will facilitate translation of positive findings in these rodent models to human studies. In summary, this project will develop rodent models of acute TETS and parathion intoxication that will be useful to the field beyond the proposed studies, and it will generate critical information on novel treatment approaches of practical value for two diverse classes of chemical threat agents. The rodenticide tetramethylenedisulfotetramine (TETS) and the organophosphorus (OP) pesticide parathion are considered credible terrorist threat agents. Current medical countermeasures for acute TETS or OP intoxication can prevent mortality but do not sufficiently protect the CNS from persistent seizures and/or permanent injury. The goal of this research project is to test the hypothesis that AMPA receptor antagonists and/or inhibitors of soluble epoxide hydrolases will significantly improve outcome following exposure to acutely toxic levels of TETS and parathion by extending the therapeutic window for seizure protection and enhancing neuroprotection
Keywords: Acute; Address; AMPA Receptors; analytical method; Animals; Anti-inflammatory; Anti-Inflammatory Agents; Anticonvulsants; Antidotes; Antiepileptic Agents; Apoptosis; Apoptotic; arm; Atropine; Attenuated; Behavioral; Benzodiazepines; Blood; Brain; Cell Death; Chemicals; Chlorpyrifos; Cholinesterases; Clinical Management; Clinical Trials; Clonic Seizure; Data; Development; Diazepam; Disulfoton; Dose; efficacy testing; Electroencephalography; emergency service/first responder; Epileptogenesis; Epoxide hydrolase; Exhibits; Exposure to; Fluoroacetates; Frequencies (time pattern); gamma-Aminobutyric Acid; Goals; Health; Hippocampus (Brain); Human; Impaired cognition; improved; inhibitor/antagonist; Injury; interest; Intoxication; Kainic Acid; Laboratories; Life; Light; Measures; Mediating; Medical; member; Military Personnel; Modeling; Monitor; Mortality Vital Statistics; Mus; National Institute of Neurological Disorders and Stroke; Neuraxis; neuroinflammation; neuron loss; Neuronal Injury; Neurons; neuropathology; neuroprotection; neurotoxicity; novel; novel therapeutic intervention; novel therapeutics; Outcome; Oximes; Parathion; Pesticides; Picrotoxin; prevent; programs; Property; rapid detection; Rattus; Relative (related person); Research; Research Project Grants; Rodent Model; Rodenticides; Safety; Screening procedure; Seizures; Severities; Slice; Sodium; Status Epilepticus; Strychnine; suicidal; Testing; tetramethylenedisulfotetramine; Therapeutic; Therapeutic Agents; Time; Tonic - clonic seizures; Toxic effect; Toxicant exposure; Translating; Translations; Treatment Efficacy; Work
Relevance: The rodenticide tetramethylenedisulfotetramine (TETS) and the organophosphorus (OP) pesticide parathion are considered credible terrorist threat agents. Current medical countermeasures for acute TETS or OP intoxication can prevent mortality but do not sufficiently protect the CNS from persistent seizures and/or permanent injury. The goal of this research project is to test the hypothesis that AMPA receptor antagonists and/or inhibitors of soluble epoxide hydrolases will significantly improve outcome following exposure to acutely toxic levels of TETS and parathion by extending the therapeutic window for seizure protection and enhancing neuroprotection
Project start date: 2010-09-30
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PAR-10-019
5R21NS072094-02 (2011): $383750
INNATE/ SIV DNA VACCINE INDUCED IMMUNITY IN THE PROTECTED MACAQUE MUCOSA
A Michael
University Of Pittsburgh At Pittsburghcity: Pittsburgh country: United States (us)
Grant 5R01AI090825-02 from National Institute Of Allergy And Infectious Diseases
Abstract: The recent report that the ALVAC-HIV prime gp120 protein (AIDSVAX B/E) boost has prevented infection in a small, but significant number of participants, provides hope that a vaccine that can prevent HIV sexual transmission is possible. This study is supported by results with other vaccines evaluated in the SIVmacaque model for AIDS, including our own using a particle mediated epidermal delivery (PMED) DNA vaccine. This vaccine prevented infection in 40% of vaccinates challenged intrarectally with a high dose of a heterologous primary SIV isolate, thereby demonstrating that immune correlates of mucosal protection observed in the SIVmacaque model will mimic mucosal protection in humans. Using a mucosal model developed by our group that enables repetitive sampling of the GALT in vaccinated macaques, we will identify the critical components of the mucosal protective immune response induced by the PMED DNA vaccine. We will test the following hypotheses (1) A vaccine confers protection not by preventing infection but by blocking virus escape from the mucosal compartment; (2) The host response to viral infection must be present at the mucosal portal of entry to prevent sexual transmission - a condition requiring direct analysis of the mucosal tissues; (3) The ability to appropriately prime and/or recall virus-specific protective immunity in the mucosa are intrinsic propert(ies) of the individual that modulate either virus replication and/or expression of defensins/chemokines comprising the mucosal innate immune system; (4) The induction of virus-specific poly-functional T cells with an effector memory T-cell phenotype recognizing a broad repertoire of epitopes in the mucosal tissues is required for mucosal protection; (5) A PMED DNA vaccine increases the breadth of the T cell responses in the gut by induction of high-avidity T cell clones that localize to the mucosal compartment. We will address these hypotheses in the following aims Aim 1 Drs. Martinson and Reinhart will directly determine the relationship of host-specific expression of mucosally relevant defensins and chemokines to vaccine-mediated protection by quantifying expression in the GALT and identifying related polymorphisms in protected and unprotected animals. Aim 2 Dr. Fuller will identify adaptive immune correlates of protection in the mucosa and determine their relationship to innate immunity. Aim 3 Dr. Murphey-Corb will determine the tripartite interplay among mucosal virus burden and escape, innate and adaptive responses, and protection induced by the PMED DNA vaccine. Together, these studies will identify novel approaches to enhance vaccine-induced protective immunity and reveal the impact of repetitive low dose (sexual) exposure on vaccine prevention. The objective of this application is to determine the molecular events that occur as a result of sexual exposure to HIV so that we may better understand why some people get infected while others do not. Understanding just what occurs at the site of initial exposure is highly relevant to the development of a vaccine that can prevent sexual transmission of HIV
Keywords: Acquired Immunodeficiency Syndrome; adaptive immunity; Address; Adjuvant; Affect; ALVAC; ALVAC Vaccine; Animals; Automobile Driving; Avidity; Binding (Molecular Function); Biological Assay; Blood; CCL20 gene; CCR5 gene; Cell physiology; Cells; chemokine; cohort; Copy Number Polymorphism; Cryopreserved Tissue; Defensins; design; Distal; DNA; DNA Vaccines; Dose; Environment; Epitopes; Event; Exhibits; Exposure to; Failure (biologic function); Gagging; Generations; Genes; Genetic; genetic analysis; Genetic Polymorphism; Gut associated lymphoid tissue; Heart; HIV; HIV Envelope Protein gp120; HIV vaccine; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunohistochemistry; In Situ Hybridization; Individual; Infection; Infection prevention; Macaca; Macrophage Inflammatory Protein-1; Measures; Mediating; Memory; Modeling; Molecular; Monkeys; Mucous Membrane; Natural Immunity; Nature; novel; novel strategies; Outcome; Participant; particle; Peptides; Phenotype; Plasma; Play; Population; Predisposition; prevent; Prevention; Process; Property; prophylactic; Proteins; RANTES; Recruitment Activity; rectal; Rectum; Reporting; research study; Resistance; response; Risk; Role; Sampling; Sexual Transmission; Sexually Transmitted Diseases; Shapes; simian immunodeficiency virus gp120; Site; SIV; Staining method; Stains; T cell response; T memory cell; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Thailand; Therapeutic Intervention; Time; tool; Transcript; Vaccinated; vaccine development; vaccine-induced immunity; Vaccines; Vagina; Viral; Virus; Virus Activation; Virus Diseases; Virus Replication
Relevance: The objective of this application is to determine the molecular events that occur as a result of sexual exposure to HIV so that we may better understand why some people get infected while others do not. Understanding just what occurs at the site of initial exposure is highly relevant to the development of a vaccine that can prevent sexual transmission of HIV
Project start date: 2010-07-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: RFA-AI-09-024
5R01AI090825-02 (2011): $745851
SOCIAL STRESS: VULNERABILITY TO COCAINE ABUSE IN MONKEYS
A Michael, Professor
Wake Forest University Health Sciencescity: Winston-salem country: United States (us)
Grant 5R37DA010584-15 from National Institute On Drug Abuse
Abstract: The overarching goal of this research is to achieve a better understanding of the individual differences in the susceptibility and vulnerability to the reinforcing effects of cocaine using a unique nonhuman primate model of drug abuse. To accomplish this, we have combined the study of primate social behavior with intravenous drug self-administration and the noninvasive brain imaging procedure positron emission tomography (PET) to examine how environmental and pharmacological variables influence the behavioral and reinforcing effects of cocaine. In the previous funding period we found that social housing altered dopamine (DA) D2 receptor function in male cynomolgus monkeys and these changes were associated with differential vulnerability to self-administer cocaine between dominant and subordinate monkeys. These studies were the first to examine intravenous cocaine self-administration in socially housed monkeys and found that social status and environmental context can have profound effects on cocaine reinforcement. We also found that chronic exposure to cocaine could attenuate the effects of social rank on DA receptor function and result in similar rates of self-administration among the socially housed monkeys. The studies proposed in this competing renewal application are designed to evaluate further the interactions between DA, social rank and the reinforcing effects of cocaine. Specifically, we propose to 1) examine further the plasticity of the DA system during cocaine abstinence and following social group reorganization and assess the impact of these manipulations on cocaine reinforcement; 2) determine the effects of social consequences of self-administering cocaine on the reinforcing effects of the drug and on measures of impulsivity; and 3) examine further the interactions between acute and chronic environmental stressors and enrichment on DA receptor function and on the reinforcing effects of cocaine, as a function of social rank. The use of novel and homologous nonhuman primate models of cocaine abuse, as proposed, should aid in understanding how environmental and pharmacological variables contribute to vulnerability, maintenance, relapse and choice behavior involving drugs of abuse. Such information will lead to better treatment and prevention strategies
Keywords: Abstinence; Acute; Address; Affect; Aggressive behavior; Animal Model; Attenuated; behavior influence; Behavioral; Brain; Brain imaging; Choice Behavior; Chronic; Cocaine; Cocaine Abuse; cocaine exposure; cocaine use; design; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; dopamine system; Drug abuse; drug abuse prevention; drug of abuse; Environment; environmental enrichment for laboratory animals; environmental stressor; Funding; Goals; Housing; Imaging Techniques; Impulsivity; Individual Differences; Intravenous; intravenous drug use; Laboratories; Lead; Macaca fascicularis; Maintenance; male; Measures; Modeling; Monkeys; Neurons; nonhuman primate; novel; Pharmaceutical Preparations; Positron-Emission Tomography; Predisposition; Prevention strategy; Primates; Procedures; Psychological reinforcement; receptor function; Recording of previous events; Relapse; Reporting; Research; Role; Self Administration; Self-Administered; social; Social Behavior; Social Functioning; social group; Social Hierarchy; Social Interaction; Social status; social stress; Stress; stressor; treatment strategy
Project start date: 1996-09-01
Project end date: 2015-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5R37DA010584-15 (2011): $502266
GENOMIC SCAN FOR ATHEROSCLEROSIS PATHWAY GENES IN AFRICAN-AMERICANS FROM FHS-SCAN
A Michael, Professor Of Genetics
Washington Universitycity: Saint Louis country: United States (us)
Grant 5R01HL088215-04 from National Heart, Lung, And Blood Institute
Abstract: The overall aim of this study is to identify genes influencing atherosclerosis as measured by coronary artery calcification (CAC), intimal medial thickness, and ankle brachial index, all quantitative measures of atherosclerotic burden, as well as endophenotypes for the atherosclerosis pathway in African-Americans. African-Americans are understudied, and yet have higher rates of many of the risk factors for atherosclerosis and CHD, lower quantitative CAC, but more hard CHD/CVD endpoints than Caucasians. We use the already collected, large (N=1,266), epidemiologically defined, longitudinal, broadly and deeply phenotyped (on all major atherosclerosis pathway domains) subjects from both the NHLBI Family Heart Study-SubClinical Atherosclerosis Network (FHS-SCAN) and the Johns Hopkins Family Heart Study. We will conduct a whole genome SNP scan, using the Illumina 650K Y-chip, which is specifically designed for subjects of African descent. We believe our family study allows optimization of several aspects of GW scan design in African- Americans. First, we will analyze the GW SNP data as an admixture map, which leverages information on individual and locus-specific ancestry, to enhance power to detect QTLs. Second, we will analyze the GW SNP data as an LD association scan, to more finely localize associated variants. Most importantly, family- based association analyses will allow us to strongly rule out false positives due to population stratification, a critical issue in African-American samples. Since the LD block structures for African-Americans are less well known than for other ethnic groups (they were not a primary target of the HapMap project), we will more finely genotype additional SNPs in hit regions, especially those in biologically plausible candidate genes, or in highly conserved regions, in order to better localize the signal. Further, we will combine the results from both the admixture map and the LD map analyses using a correlated meta-analysis technique. Our GW mapping approach has high power to detect any gene explaining at least 2-5% of a trait in the atherosclerosis pathway, through ht-SNPs that are at least within R2=0.80 of a functional variant. With the wealth of phenotypic characterization of FHS+JHFHS African-American subjects in pedigrees and the available linkage results, a genome-wide association scan would allow rapid and efficient discovery of genes related to the development of atherosclerosis in humans. Such findings would be of great significance they could enhance our understanding of the metabolic and mechanistic processes that lead to atherosclerosis and coronary endpoints and, thereby, suggest possible points of intervention or therapy in the understudied, but high risk African- American population
Keywords: Accounting; Admixture; African; African American; Ankle; Atherosclerosis; base; Biological; Blood Pressure; Boston; Budgets; Candidate Disease Gene; Cardiovascular Diseases; Caucasians; Caucasoid Race; Chromosome Mapping; Clinical; Coronary Arteriosclerosis; coronary artery calcification; Coronary heart disease; cost effective; Data; design; Development; Diabetes Mellitus; endophenotype; Ensure; Ethnic group; Family; Family member; Family Study; follow-up; Funding; gene discovery; Genes; genetic pedigree; Genome; genome wide association study; genome-wide; Genomics; Genotype; Haplotypes; Heart; high risk; Human; indexing; Individual; Inflammation; interest; Intervention; Lead; Link; Linkage Disequilibrium; Linkage Disequilibrium Mapping; Lipids; Lipoproteins; Location; Maps; Measures; Medial; Meta-Analysis; Metabolic; Metabolic syndrome; Methods; Microsatellite Repeats; Minority; Modeling; National Heart, Lung, and Blood Institute; Obesity; Partner in relationship; Pathway interactions; Phenotype; Population; Probability; Process; programs; Province; public health medicine (field); Publishing; Randomized; Recombination Fraction; Recording of previous events; research study; Resolution; Resources; Risk Factors; Running; Sampling; Scanning; Signal Transduction; simulation; Source; Staging; statistics; Stratification; Structure; Techniques; Testing; Thick; trait; Universities; Variant; Washington
Project start date: 2008-05-15
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01HL088215-04 (2011): $744586
EXTRINSIC SIGNALING IN THE HOMEOSTATIC REGULATION OF OLFACTORY NEUROGENESIS
A Michael
Johns Hopkins Universitycity: Baltimore country: United States (us)
Grant 5F30DC009542-04 from National Institute On Deafness And Other Communication Disorders
Abstract: The olfactory epithelium (OE) is one of the few tissues in adult animals that retains the remarkable ability to produce new neurons throughout the lifetime of the animal. This continual neuronal production is highly regulated and permits the replacement of olfactory sensory neurons (OSNs) that reach the end of their limited lifespan. Selective ablation of the entire mature OSN population induces proliferation of multipotent progenitors in the basal epithelium and the rapid replenishment of the depleted neuronal cells. These observations suggest a model in which mature neurons negatively regulate proliferation, and the loss of this neuron-derived feedback signal promotes the repopulation of the neuronal repertoire. GDF11, a member of the TGF-beta superfamily, is a strong candidate as a factor that neurons secrete to inhibit proliferation. This was discovered in studies examining its effects on proliferating OSN cell cultures, and a genetic mouse model in which it was knocked out. These observations were limited to embryonic tissue, because GDF11 knockout mice have defects in the development of multiple organ systems, rendering them inviable after birth. However, to know what role this candidate is playing in the exquisitely regulated neurogenesis in adult OE, GDF11 must be studied in the adult. The proposed research will provide a comprehensive examination of the role that this and closely-related factors play in the adult OE. First, a variety of labeling studies will be employed to identify the specific cells that send and receive this signal throughout the lifetime of the animal. Two distinct genetically-modified mouse lines will also be generated by crossing existing lines that will allow investigation of this system in the adult. The first will be a conditional knockout, which will use cre-lox technology to eliminate GDF11 function exclusively in the OE, allowing the normal development of other organ systems. The second line will utilize the tet modulation system allowing us to induce expression of follistatin, a GDF11 antagonist, at any time in the life of the animal. In both of these models, we can examine how blocking this pathway will alter proliferation and cell type composition in the OE. These experiments can easily be expanded to investigate the well-known decline in olfaction with age, as evidence suggests this may be related to decreases in neurogenesis. RELEVANCE An age-related decline in olfaction leads to a decrease in the quality of life in a high proportion of the elderly. Evidence suggests that this may be related to a decreased turnover of odorant detecting neurons. Understanding the signals that modify this turnover (and how they change with age) may help us identify the cause of this decline in olfaction, and may identify targets for preventing or treating it
Keywords: 2-Naphthacenecarboxamide, 4-(dimethylamino)-1, 4, 4a, 5, 5a, 6, 11, 12a-octahydro-3, 5, 10, 12, 12a-pentahydroxy-6-methyl-1, 11-dioxo-, (4S-(4alpha, 4aalpha, 5alpha, 5aalpha, 6alpha, 12aalpha))-; 21+ years old; Ablation; Activin-Binding Protein; Acute; Adult; adult animal; adult human (21+); advanced age; Adverse Late Effects; Afferent Neurons; Age; age dependent; age related; aged; Aged 65 and Over; Aging; alpha-6-Deoxyoxytetracycline; Animals; Autoregulation; balance; balance function; biological signal transduction; Birth; body system; Body Tissues; Bone-Derived Transforming Growth Factor; Cell Communication and Signaling; Cell Culture Techniques; Cell Differentiation; Cell Differentiation process; Cell Growth in Number; Cell Multiplication; Cell Proliferation; Cell Signaling; cell type; Cells; Cellular Proliferation; Defect; Development; Doxycycline; Education; Educational aspects; Elderly; Elderly, over 65; elders; Embryo; Embryo Development; embryo tissue; Embryogenesis; Embryonic; Embryonic Development; Embryonic Tissue; Epithelium; Equilibrium; Exhibits; experiment; experimental research; experimental study; extracellular; Family; Family member; Feedback; Follistatin; Fostering; Genetic; Genetic Models; geriatric; Goals; heavy metal lead; heavy metal Pb; Homeostasis; Human, Adult; information gathering; interest; Intracellular Communication and Signaling; Investigation; Knock-out; Knockout; Knockout Mice; Label; Laboratories; Late Effects; late life; later life; Lead; Length of Life; Life; life span; lifespan; Longevity; Maintenance; Maintenances; Mammals, Mice; mature animal; Mediating; Medicine; member; Mice; Mice, Knock-out; Mice, Knockout; Milk Growth Factor; Modeling; Molecular; Molecular Genetic; Molecular Genetics; mouse model; Mouse Strains; multipotent progenitor; Multipotent Stem Cells; Murine; Mus; Nerve Cells; Nerve Unit; Neural Cell; Neural Growth; neurobiological; Neurobiology; Neurocyte; neurogenesis; neuron cell death; neuron loss; neuronal; neuronal cell death; Neuronal Growth; neuronal loss; Neurons; Neurons, Afferent; Neurons, Sensory; Null Mouse; older adult; older person; Olfaction; Olfactions; Olfactory Epithelium; Organ System; Parturition; pathway; Pathway interactions; Pattern; Pb element; Perinatal; Phenocopy; Physicians; Physiological Homeostasis; Platelet Transforming Growth Factor; Play; Population; prevent; preventing; Production; Proliferating; QOL; Quality of life; Regulation; Research; research study; Role; Science; Science of Medicine; Scientist; Senescence; senescent; senior citizen; Sensory; Sensory Cell Afferent Neuron; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Molecule; Smell; Smell Perception; social role; sustentacular cell; System; System, LOINC Axis 4; Technology; Tet; Tetanus Helper Peptide; TGF B; TGF-beta; TGFbeta; Time; Tissues; Training; Transforming Growth Factor beta; Vibramycin
Project start date: 2008-02-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-05-151
5F30DC009542-04 (2011): $46380
A Michael
Ohio State Universitycity: Columbus country: United States (us)
Grant 2P30CA016058-35 from National Cancer Institute
Abstract: The Ohio State University Comprehensive Cancer Center (OSUCCC) is currently in its 35th year as an NCI designated CCC and is now requesting continued federal support for the next five years. Dr. Caligiuri currently continues in his seventh year as the OSUCCC Director and has since been named CEO of OSU´s freestanding James Cancer Hospital. The overall goal remains to reduce cancer morbidity and mortality through continued basic, translational and clinical research. The 239 OSUCCC full, associate or introductory members are currently served by 18 shared resources and are distributed among the our six Research Programs which remain unchanged Cancer Control, Experimental Therapeutics, Innate Immunity, Molecular Biology and Cancer Genetics, Molecular Carcinogenesis and Chemoprevention, and Viral Oncology. Since the last competitive renewal, the OSUCCC has shown significant growth as demonstrated by 1) the recruitment of 159 faculty focused in basic, translational and clinical cancer research and medicine; 2) more than a 80% increase in patient accrual to investigator-initiated trials; 3) the addition of 5 new shared resources at an institutional investment of over $4.2 million; 4) a 96% increase in total NCI funding despite a period of relatively flat federal funding; 5) an 85% increase in publications, 51% of which were collaborative (i.e., inter-, intra-programmatic, or both); 5) discovery, preclinical development and administration of two new anti-cancer agents into man, along with additional important advances in basic and clinical cancer research. The OSUCCC has also seen tremendous growth in institutional commitment since 2004 as demonstrated by 1) a ten-fold increase in annual financial support (now approximately $50 million) for the OSUCCC under the control of the Director; 2) an additional $7.0 million of cash annually from OSU for research and infrastructure expansion; 3) a formal direct reporting relationship to the Executive Vice President and Provost with complete oversight of the University-wide cancer funding initiatives, opportunities and cancer grant submissions; 4) A seat on the University President´s cabinet providing representation of the CCC at the highest level of the University; 5) a six-fold increase in space currently under the sole control of the Director, including new additional dry and wet laboratory and office space for recruitment of additional faculty; 6) a written commitment and approval by the OSU Board of Trustees for the expansion of the Cancer Program facilities that will more than double the current square footage under control of the OSUCCC Director in the next five years at a cost of approximately $800 million. With these new resource commitments in place, the OSUCCC is poised for continued significant growth and expansion in the next 5 years
Keywords: anticancer research; Antineoplastic Agents; Area; Award; Basic Science; Cancer Center Support Grant; Cancer Control; cancer genetics; Cancer Hospital; cancer research center director; Chemoprevention; Clinical; Clinical Research; Collaborations; Comprehensive Cancer Center; cost; design; Development; Faculty; Financial Support; Funding; Goals; Grant; Growth; Hematologic Neoplasms; Investments; Laboratories; Leadership; Legal patent; Malignant Neoplasms; man; Medicine; meetings; member; Molecular Biology; Molecular Carcinogenesis; Morbidity - disease rate; Mortality Vital Statistics; Names; Natural Immunity; Ohio; oncology; Patients; Phase; Physicians; pre-clinical; programs; Publications; Reporting; Research; Research Infrastructure; Research Personnel; Resource Sharing; Resources; Scientist; SECTM1 gene; Solid Neoplasm; Strategic Planning; success; Therapeutic; Time; TNFRSF5 gene; Translational Research; Trustees; Universities; Viral; Writing
Project start date: 1997-09-12
Project end date: 2015-11-30
Budget start date: 5-AUG-2011
Budget end date: 30-NOV-2011
2P30CA016058-35 (2011): $4582303
3P30CA016058-35S2 (2011): $49250
3P30CA016058-35S3 (2011): $140000
UNIVERSITY OF WASHINGTON "STAR" PROGRAM
A Michael
University Of Washingtoncity: Seattle country: United States (us)
Grant 5R25HL103180-02 from National Heart, Lung, And Blood Institute
Abstract: The objectives of are 1. to identify and encourage a diverse pool of underrepresented students to participate in biomedical research; 2. to increase the academic/experiential capabilities of participating students; 3. strengthen students´ competitiveness (and interest in) entering graduate/professional health-related research degree programs; and, 4. to increase diversity in NHLBI-focused research (i.e., cardiology, pulmonary, hematology, and sleep). In the past 10 years, the Program has become proficient in identifying, attracting, and training undergraduate students who have successfully pursued graduate and professional degrees in the sciences and health professions. Based on current literature, and having demonstrated its capacity to support undergraduate students, the UW STAR Program proposes to expand its training pool to include students who have completed their first-year of medical or professional school. Training both undergraduate and medical/professional level students, the Program will place research interns into faculty mentored biomedical, behavioral and clinical laboratories for a period of 2 to 3 months. The various laboratory sites are located at the University of Washington and in the Seattle-area, with all faculty affiliated with the University of Washington. Interns in the Program will also receive biomedical laboratory safety training; participate in two multi- week workshops and, finally will present their findings in an end-of-program Poster Session. Those undergraduate students, who the Program staff believes would benefit from extended research experiences, will be invited to return for a second research summer. We believe the strength of the UW STAR Program is represented by the large number of participants who have received PhDs, MD- PhDs, and other degrees in other areas of science and the health professions. The professional student initiative will help to increase the numbers of professional level students who have a strong interest and are prepared to pursue an academic medicine track with an emphasis on underrepresented communities and their health in relation to cardiology, pulmonary, hematology, and/or sleep clinical research. The UW STAR Program will help expand the numbers of individuals from diverse groups selecting biomedical/behavioral educational, research, and/or career paths. Participation by individuals underrepresented in the biomedical and behavioral sciences will to lead to better research and health-related outcomes for individuals in underserved, diverse communities. (End of )
Keywords: ing; Area; base; Behavior; Behavioral; Behavioral Research; Behavioral Sciences; Biomedical Research; Cardiology; career; Clinical; Clinical Research; Communities; Educational workshop; experience; Faculty; Goals; Health; Health Occupations; Health Professional; Hematology; Individual; interest; Laboratories; Laboratory Research; Lead; Literature; Lung; Medical; Medicine; Mentors; National Heart, Lung, and Blood Institute; Outcome; Participant; Pathway interactions; Population Heterogeneity; posters; programs; Recruitment Activity; Research; Research Personnel; Safety; Schools; Science; Scientist; Site; skills; Sleep; Sleep Disorders; Students; success; Time; Training; Underrepresented Minority; Universities; Washington
Relevance: UW STAR - The UW STAR Program will help expand the numbers of individuals from diverse groups selecting biomedical/behavioral educational, research, and/or career paths. Participation by individuals underrepresented in the biomedical and behavioral sciences will to lead to better research and health-related outcomes for individuals in underserved, diverse communities
Project start date: 2010-06-01
Project end date: 2015-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: RFA-HL-10-013
5R25HL103180-02 (2011): $169154
Sponsored Links Excellgen http://Excellgen.com
A Michael
Hugo W. Moser Res Inst Kennedy Kriegercity: Baltimore country: United States (us)
Abstract: The Neuroimaging Core has been a part of the MRDDRC since the Center was first established, in 1987. The Core was initially under the directorship of Dean Wong, M.D., Ph.D. Reflecting both Dr. Wong´s areas of expertise as well as the prevailing neuroimaging techniques at the time, during its first five years of operation the Neuroimaging Core focused substantial resources on development and refinement of positron emission tomography (PET) methods for qualitative and quantitative assessments of CMS neurotransmitter receptors. Over the next five years, as reflected in the 1993 resubmission for the second five-year funding period, the number of radioligands in use or under investigation had increased, and included ligands that could be used to assess receptors for opiates, for dopamine, for benzodiazepines, and for serotonin. While the Core also facilitated access to expertise in anatomic MRI and magnetic resonance spectroscopy (MRS), these areas were less well represented then they are now. MRS was largely constrained to spatially rather coarse single voxel studies, and spatial co-registration of multiple anatomic MRI studies to common templates for the purposes of quantifying morphologic differences between brains or for localizing lesions to specific regions was in its relative infancy
Keywords: Anatomy; Area; Behavior; Benzodiazepines; Brain; Brain region; Characteristics; Clinical; Cognitive; Complement; Data Analyses; Development; Doctor of Medicine; Doctor of Philosophy; Dopamine; Equilibrium; experience; Functional Imaging; Functional Magnetic Resonance Imaging; Funding; Imaging Device; infancy; Investigation; Ligands; Localized Lesion; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mental Retardation and Developmental Disabilities Research Centers; Mission; morphometry; neuroimaging; Neurosciences; Neurotransmitter Receptor; operation; Opioid Receptor; Performance; Physiologic pulse; Positron-Emission Tomography; Protocols documentation; Qualitative Methods; radioligand; Relative (related person); Research; Research Personnel; Resolution; Resources; Serotonin; Stimulus; Techniques; Technology; Thinking, function; Time; tool; Training; Transcranial magnetic stimulation; white matter
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P30HD024061-24_9004 (2011): $319135
PROSTAGLANDINS IN C. ELEGANS FERTILIZATION
A Michael, Assistant Professor
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Grant 5R01GM085105-04 from National Institute Of General Medical Sciences
Abstract: The molecular mechanisms of prostaglandin action are of considerable importance to reproductive biologists, immunologists, neurobiologists, and oncologists. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) specifically inhibit prostaglandin synthesis and are associated with cancer prevention and reversible infertility. Prostaglandins are essential for ovulation and fertilization, but the molecular mechanisms are not well understood. The mouse is the only genetic system currently available to study prostaglandin functions during reproduction. The objective of this application is to determine the extent to which the nematode model Caenorhabditis elegans can be used to address fundamental questions in prostaglandin biology. To achieve this objective, we will test the central hypothesis that oocytes synthesize prostaglandins to regulate ovulation and sperm guidance. Support for this hypothesis comes from preliminary data showing that prostaglandin precursors, polyunsaturated fatty acids (PUFAs), and predicted prostaglandin synthases are required for these processes. In addition, prostaglandins can regulate sperm motility in the absence of PUFAs. Our first aim is to delineate a prostaglandin biosynthesis pathway that functions in oocytes. To achieve this aim, we will characterize predicted prostaglandin biosynthesis enzymes at the genetic and biochemical levels. Our second aim is to determine the extent to which prostaglandins and NSAIDs influence fertilization. To achieve this aim, we will examine the effects of prostaglandins and NSAIDs on sperm motility and ovulation in vivo. Our final aim is to identify the PUFA-derived signals synthesized by oocytes. A combination of genetics and liquid chromatography coupled to electrospray ionization tandem mass spectrometry will be used to achieve this aim. We expect that completing the proposed aims will establish the C. elegans gonad as the first simple, genetically tractable model for discovering molecular mechanisms of prostaglandin action during reproduction. These studies should lead to a comprehensive delineation of genes that are required for prostaglandin synthesis and function, any of which could encode new drug targets. The role of prostaglandins in fertilization could be conserved in mammals, an idea supported by prostaglandin deficient mice. Regardless, basic research on prostaglandins in the C. elegans gonad has the potential for discovering molecular mechanisms of human infertility, contraception, and cancer. Prostaglandins are lipid signals that are critical for human reproduction, immunity, and cardiovascular functions. Basic research on prostaglandins in the ovary has the potential for discovering molecular mechanisms of cancer, infertility, and contraception. The objective of this proposal is to determine the extent to which the model system Caenorhabditis elegans can be used to elucidate the molecular mechanisms of prostaglandin action during reproduction
Keywords: Address; Affect; Anabolism; Animal Model; Anti-inflammatory; Anti-Inflammatory Agents; Aspirin; base; Basic Science; Biochemical; Biochemical Genetics; Biological; Biological Assay; Biological Models; Biology; Birth; Caenorhabditis elegans; cancer prevention; Cardiovascular Physiology; cell motility; Complement; Complex; Contraceptive methods; Coupled; Cytochrome P450; Data; Decidual Cell Reactions; Defect; Deuterium; Dietary Supplementation; Drug Delivery Systems; Electrospray Ionization; Endocytosis; enzyme biosynthesis; Enzymes; Event; expectation; Female; Fertilization; Genes; Genetic; Goals; Gonadal structure; Health; Human; Immunity; Immunologist; implantation; In Vitro; in vivo; Infertility; innovation; Intestines; Label; Lead; Learning; Letters; Leukotrienes; Lipid Chemistry; lipid structure; Lipids; Lipoproteins; Liquid Chromatography; Low Density Lipoprotein Receptor; Malignant Neoplasms; Mammals; Mass Spectrum Analysis; Measures; Mediating; Methods; Microinjections; Modeling; Molecular; Molecular Genetics; Mus; Nematoda; Oncologist; Oocytes; Ovary; Ovulation; Pathway interactions; Pharmaceutical Preparations; Polyunsaturated Fatty Acids; Process; Prostaglandin D2; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Proteins; Publishing; Reproduction; reproductive; Reproductive Biology; research study; RNA Interference; Role; Signal Transduction; Signaling Molecule; Site; Source; sperm cell; Sperm Motility; System; tandem mass spectrometry; Testing; Work
Project start date: 2008-07-01
Project end date: 2013-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01GM085105-04 (2011): $243303
MUCOSAL REOVIRUS-ADENOVIRUS VACCINES AGAINST HIV-1
A Michael, Professor
Mayo Cliniccity: Rochester country: United States (us)
Grant 5R01AI065304-04 from National Institute Of Allergy And Infectious Diseases
Abstract: The majority of HIV-1 infections occur at mucosal surfaces in the body. There is therefore an immediate need for potent HIV vaccines that can provide barrier protection at mucosal surfaces. While there is this need, most HIV vaccines have been developed and tested for their ability to drive systemic immune responses and not for mucosal responses. Given that systemic immunization generally does not provoke potent mucosal protection, this project will develop adenoviral gene delivery vectors targeted to specifically drive potent mucosal immune responses. This project will pursue this goal in the following Aims Specific Aim 1. Generate New Fiber-Sigma Chimeras and Test Their Functionality In Vitro. Specific Aim 2. Test Ad-Sigma Vaccines for Their Ability to Enhance Mucosal Immunization Specific Aim 3. Determine the Role of Sigma 1 Motifs in Viral Uptake, Transduction, and Vaccination. Specific Aim 4. Test Methods to Maximize Mucosal Prime-Boost Strategies with Ad-Sigma Vaccines. This project will test both traditional replication-defective adenovirus type 5 (Ad5) vectors and Ad vectors engineered with reovirus sigma 1 protein (Ad-Sigma1) for their ability to drive mucosal immune responses against HIV-1 gag. This project will test if Ad-Sigma1 is able to enhance mucosal immunization after administration by intranasal and oral administration by virtue of its ability to target junctional adhesion molecule 1 (JAM1) and sialic acid, two receptors that are expressed on mucosal surfaces and on M cells. We will test if this mucosal-targeting vaccine targets immunologically-relevant mucosal dendritic cells, mucosal epithelial cells, and M cells to maximize mucosal vaccine efficacy and reduce side effects due to interactions with cells that do not contribute to vaccination. We will also analyze the key dependence of sigma 1 ligands and other features in mediating uptake of virions into these sites. These approaches will be tested in humanized HLA-A*0201 transgenic mice to give guidance for future human tests. Successful pursuit of this project will enable more specific and less dangerous adenoviral vaccines. This project will provide vaccine efficacy and safety data for these three Ad vaccine approaches in mice as a precursor to testing in rhesus macaques and in humans
Keywords: Address; Adenoviruses; Adverse effects; Animals; Antibodies; base; Biological Assay; Budgets; Cell Count; Cells; Chimera organism; Clinic; Conflict (Psychology); Data; Data Analyses; Dendritic Cells; Dependence; design; Engineering; Ensure; enzyme linked immunospot assay; Epithelial Cells; Fiber; Funding; Future; Gagging; Gene Delivery; Goals; HIV vaccine; HIV-1; HLA A*0201 antigen; Human; Immune; Immune response; Immunity; Immunization; immunogenicity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin-Secreting Cells; Immunoglobulins; Immunology; improved; In Vitro; in vivo; Individual; Infection; interest; Intranasal Administration; Irrigation; junctional adhesion molecule; Laboratories; Ligands; Liquid substance; Lymphocyte; M cell; Macaca mulatta; Measures; Mediating; Methods; Mucosal Immune Responses; mucosal vaccine; Mucous Membrane; Mus; National Institute of Allergy and Infectious Disease; Oral Administration; Pan Genus; Peptide Hydrolases; Policies; Procedures; Proteins; Published Comment; Reagent; receptor; Recruitment Activity; reovirus minor outer capsid protein; Reovirus sp.; Research Design; Research Personnel; research study; response; Role; Running; Secretory Component; Secure; Serotyping; Serum; Sialic Acids; Site; Specimen; Surface; Techniques; Testing; Text; Tissues; Transgenic Mice; Transudate; Travel; United States National Institutes of Health; uptake; Vaccination; vaccine efficacy; vaccine safety; Vaccines; vector; vector-induced; Viral; Virion; Visit; Wages; Work; Writing
Project start date: 2007-12-15
Project end date: 2011-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PA-07-070
5R01AI065304-04 (2011): $370233
NEURAL MECHANISMS OF PERCEPTUAL LEARNING IN THE HUMAN BRAIN
A Michael, Assistant Professor
University Of California Berkeleycity: Berkeley country: United States (us)
Grant 5R21EY019992-02 from National Eye Institute
Abstract: The long-term objective of this project is to characterize neural correlates of perceptual learning in the human visual system. Perceptual learning can be defined as a specific improvement in the performance of a perceptual discrimination through training. Humans are capable of learning new and intricate skills throughout the lifespan, and perceptual learning experimental paradigms provide model systems for studying these processes. In addition, training procedures involving perceptual learning have been used to treat learning disorders like dyslexia and developmental disorders such as amblyopia. Therefore, understanding the neural mechanisms underlying perceptual learning has consequences for basic science as well as public health implications. Two perceptual learning tasks will be employed in these studies a motion direction discrimination task and a texture orientation discrimination task. These tasks differentially involve two different visual processing streams in the human brain. One of these specialized for perception of motion and spatial location, and the other is specialized for perception of visual form. Human subjects will be trained on these tasks, and the improvements in behavioral performance resulting from this training will be measured. To study neural correlates of this enhancement in behavioral performance, functional magnetic resonance imaging (fMRI) will be used to measure the activity in defined brain areas before and after perceptual learning occurs. The fMRI experiments will include measurements of the amplitude of responses evoked by visual stimuli and estimates of selectivity of populations of neurons in a number of cortical areas. [Changes in functional connectivity among these areas following perceptual learning will also be measured.] Selectivity will be defined in the spatial domain and in the featural domain (selectivity for stimulus orientation or direction of motion). Acetylcholine is a neurotransmitter that plays an important role in attention networks in the brain. Drugs that prolong the synaptic actions of endogenous acetylcholine (cholinesterase inhibitors) are the most common treatment of Alzheimer´s disease. Although the actions of these drugs at the biochemical level are well characterized, their cognitive effects and neural correlates of these effects are poorly understood. The cholinesterase inhibitor donepezil (trade name Aricept) will be administered during the perceptual learning training procedures to shed light on the role of acetylcholine on learning neural plasticity and to better understand the mechanisms by which these drugs improve cognitive function in patients with Alzheimer´s disease. We will use magnetic resonance imaging (MRI) to measure brain activity in healthy human subjects before and after they undergo a training procedure that improves their ability to make visual discriminations. A variety of MRI measurements will be made to characterize the changes that take place in the brains of subjects as a result of this learning. In addition, the subjects will be administered donepezil, an Alzheimer´s medication known to enhance cognition, and the effects of this drug on the perceptual and brain correlates of learning will be determined
Keywords: Acetylcholine; Address; Adult; Alzheimer`s Disease; Amblyopia; Animal Model; Area; Aricept; Attention; Basic Science; Behavioral; Biochemical; Biological Models; Brain; Cells; cholinergic; Cholinesterase Inhibitors; Cognition; Cognitive; cognitive function; common treatment; Coupling; Crossover Design; Decision Making; developmental disease/disorder; Discrimination (Psychology); donepezil; Double-Blind Method; Drug effect disorder; Dyslexia; Exhibits; extrastriate visual cortex; Functional Magnetic Resonance Imaging; Gold; Human; human subject; improved; Laws; Learning; Learning Disorders; Light; Location; Longevity; Magnetic Resonance Imaging; Maps; Measurement; Measures; Metabolic; Methods; Modality; Motion; Motion Perception; Names; neuromechanism; Neuronal Plasticity; Neurons; Neurotransmitters; Parietal; Parietal Lobe; Patients; Perceptual learning; Performance; Pharmaceutical Preparations; Photic Stimulation; Physiological; Placebo Control; Play; Population; Procedures; Process; Property; Psychophysiology; public health medicine (field); public health relevance; relating to nervous system; Relative (related person); Reporting; Research; research study; Resolution; response; retinotopic; Role; Sensory; sensory cortex; skills; Space Perception; Specificity; Stimulus; Stream; Synapses; System; Testing; Texture; Training; Visual; Visual Cortex; Visual Fields; Visual Perception; visual process; visual processing; visual stimulus; Visual system structure; young adult
Relevance: We will use magnetic resonance imaging (MRI) to measure brain activity in healthy human subjects before and after they undergo a training procedure that improves their ability to make visual discriminations. A variety of MRI measurements will be made to characterize the changes that take place in the brains of subjects as a result of this learning. In addition, the subjects will be administered donepezil, an Alzheimer´s medication known to enhance cognition, and the effects of this drug on the perceptual and brain correlates of learning will be determined
Project start date: 2010-09-01
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-09-164
5R21EY019992-02 (2011): $221040
PROTEIN MICROARRAY SYSTEM FOR RHEUMATOID ARTHRITIS
A Michael
Ciencia, Inc.city: East Hartford country: United States (us)
Grant 5R44AI066482-03 from National Institute Of Allergy And Infectious Diseases
Abstract: The long-term objective of the proposed effort is to develop an autonomous clinical diagnostics system for monitoring normal and diseased immune function that occurs in the context of rheumatoid arthritis, infection, inflammation, asthma, autoimmune disease, and neoplasia. This system will be a microarray-based bioassay platform that specifically captures distinct cell types and soluble macromolecules from a patient´s blood sample onto spatially separate regions on a biosensor chip. Initial capture of macromolecules and cells can be quantified to assess the presence of specific subpopulations of leukocytes, cytokines, antibodies and other immunologically relevant molecules. Subsequent culture of the captured cells under different conditions can be used to measure the production of specific cell products in real time to assess immune cell functional capacities. The technology allows for highly parallel measurements that result in the capability to perform hundreds of individual functional cellular assays simultaneously without the use of molecular labels. The system will enable assessment of patients´ immune capacity in near-real time using microliter-scaled samples of blood readily harvested with minimally invasive procedures (e.g., fingerstick capillary blood sampling). Such real-time measurements will be crucial for the ongoing monitoring of disease progression as well as the evaluation of prophylactic treatments and therapeutic manipulations that sustain and support immune mechanisms. This project will develop tools that will enable improved diagnostics for rheumatoid arthritis, autoimmune diseases, and for infectious diseases
Keywords: Activities of Daily Living; Americas; Animals; Antibodies; Antioxidants; Area; Asthma; Autoimmune Diseases; Award; base; Biological; Biological Assay; Biological Models; biomarker; Biosensor; Blood capillaries; Blood specimen; borage oil; Buffers; capillary; Cell physiology; cell type; Cells; Cellular Assay; Cellular Compartment Analysis; Clinical; Clinical Trials; Communicable Diseases; Computational algorithm; Coupled; cytokine; Data; Data Analyses; Data Set; design; design and construction; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Management; Disease Progression; Drug Formulations; Early Diagnosis; established cell line; Evaluation; experience; Experimental Models; Fish Oils; Fluorescence; Goals; Gold; Harvest; Human; Image; Immune; immune function; improved; Individual; Infection; Inflammation; instrument; instrumentation; interest; Label; Laboratories; Laboratory Research; Letters; Leukocytes; Longevity; macromolecule; Market Research; Marketing; Measurement; Measures; minimally invasive; Molecular; Molecular Target; Monitor; Mus; Neoplasms; novel; Onset of illness; Patient Monitoring; Patients; Performance; Phase; Phase III Clinical Trials; Phenotype; Plasma; point-of-care diagnostics; Procedures; Production; programs; Prophylactic treatment; Protein Microchips; Proteins; Protocols documentation; prototype; public health relevance; Reagent; Recruitment Activity; Research; Research Personnel; research study; response; Rheumatoid Arthritis; Rheumatology; Sampling; sensor; Series; Small Business Innovation Research Grant; Surface; Surface Plasmon Resonance; System; Systems Analysis; Technology; Therapeutic; Therapeutic Intervention; Time; time use; tool
Relevance: 7. This project will develop tools that will enable improved diagnostics for rheumatoid arthritis, autoimmune diseases, and for infectious diseases
Project start date: 2005-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-09-080
5R44AI066482-03 (2011): $484915
A Michael, Associate Professor
Baylor College Of Medicinecity: Houston country: United States (us)
Abstract: The Integrated Microscopy Shared Resource (IMSR) is a state-of-the-art equipment, training, and consultation imaging resource resource for scores of Dan L. Duncan Cancer Center (DLDCC) researchers. Its mission is to provide a full suite of light and electron microscopy (LM, EM), and assay development resources for DLDCC and other BCM investigators. The IMSR staff is well-trained in all aspects of image based investigation and stays at the forefront of new experimental approaches in collaboration with the IMSR leader´s research program. The IMSR currently supports image-based studies for both live and fixed cells using manual and automated high throughput microscopy (HTM), and also for ultrastructural studies via transmission EM. The LM resources consist of a new Nikon AIR multispectral and Zeiss LSM 510 META confocal microscopes. A new DeltaVision "Core" deconvolution scope and a thoroughly-upgraded original DeltaVision are now in use along with a Zeiss AxioPlan2/CCD workstation. The Nikon and DeltaVison Core instruments are fully live cell and FRET capable, and both are suitable for multiwell plate usage. Standard HTM capabilities are based upon the two fully-automated Beckman-Coulter IC-100 systems with robotic platforms for fluid handling and plate loading. High content analysis (HCA) support is based upon the fully customizable Pipeline Pilot image analysis platform. HTM and automated image processing are synergistic with primary screening of monoclonal antibodies (Proteomics Shared Resource), and RNAi libraries (RNAi Shared Resource) for high speed pathway analysis in single cell assays. The Hitachi H-7500 transmission digital EM supports ultrastructural studies. IMSR staff include two imaging technologists and a registered electron microscopy technician. IMSR goals are to facilitate and support DLDCC researchers through collaboration on experimental design, user training on all instrumentation and software, and as needed, direct image acquisition or processing by IMSR staff, and assistance in data interpretation and presentation. The IMSR will continue to expand to meet DLDCC needs through equipment grants and vendor arrangements in order to provide Cancer Center investigators with basic and leading-edge imaging infrastructure and expertise
Keywords: Address; anticancer research; assay development; Automation; base; Biological Assay; Biometry; Brightfield Microscopy; Cancer Biology; Cancer Center; Cancer Center Support Grant; cell fixing; Cells; Cellular biology; Collaborations; Collection; college; Complex; Computer software; Consultations; cost; Data; Development; digital; digital imaging; Electron Microscopy; Equipment; Experimental Designs; Experimental Models; Faculty; Fluorescence Microscopy; Fluorescence Resonance Energy Transfer; Generic Drugs; genome-wide; Goals; Grant; Health Services Accessibility; high standard; high throughput screening; Housing; Human Resources; Image; Image Analysis; image processing; Informatics; Institution; instrument; instrumentation; Investigation; Laboratories; Laboratory Research; Laser Scanning Confocal Microscopy; Libraries; Life; light microscopy; Liquid substance; Location; Malignant Neoplasms; Manuals; Medical Research; Medicine; meetings; member; Microscope; Microscopy; Mission; Molecular and Cellular Biology; Monoclonal Antibodies; operation; Optics; Pathway Analysis; Process; programs; Proteomics; Proteomics Shared Resource; Recording of previous events; repository; Reproductive Biology; Research; Research Infrastructure; Research Personnel; Resolution; Resource Sharing; Resources; RNA Interference; Robotics; Scientist; Screening procedure; Services; Speed (motion); System; Systems Biology; Techniques; Technology; Tissues; tool; Training; Transmission Electron Microscopy; transmission process; Vendor; Work
Relevance: Microscopy has been, and will continue to be, an indispensable research and medical tool in the field of cancer biology. The Integrated Microscopy Shared Resource provides Cancer Center scientists an invaluable access to a state-of-the art collection of imaging and technical resources that can enable them to excell in their cancer research
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P30CA125123-05_6481 (2011): $85616
CORE D - INTEGRATED MICROSCOPY CORE
A Michael, Associate Professor
Baylor College Of Medicinecity: Houston country: United States (us)
Abstract: The Integrated Microscopy Core has been an important resource for this U54 Center for Reproductive Biology from its inception over 35 years ago. The Core, enabling routine and sophisticated light microscopy (LM) and electron microscopy (EM), has significantly supported all four Projects in the last funding period, and continues to be an integral support component of the current proposal. The Core has provided LM and EM resources, training and services for a wide range of biological projects. These include the longstanding general imaging of histological and ultrastructural specimens, and over the years has evolved to provide an increasing number of integrated image-based approaches that bring together biochemistry, cell biology, molecular and genetic studies (e.g., interaction, expression levels, immunological, epitope-tagging, reporter gene studies, etc). The most recent technological shift has been to increased implementation of automation and highly quantitative functional and cytological measurements obtained through the installation of high throughput microscopy (HTM) equipment. Effectively, the ability of the Integrated Microscopy Core now provides not only the routine and advanced imaging resource, but is increasingly bringing to the forefront high throughput systems biology as a Research & Development tool to bring new technologies to the U54 Projects. HTM will be critical for the investigators in this U54 application. The focus of the research in this U54 renewal application is the investigation of the role of co-regulators, transcription factors, cell signaling and micro RNA in the regulation of endometrial and ovarian function in the mouse and human. All these approaches will utilize imaging as a tool to evaluate endometrial biology. The execution of the aims of these projects will require the core to be an evolving tool
Keywords: Automation; base; Biochemistry; Biological; biological research; Biology; Cellular biology; Computer software; Consult; Data Analyses; Electron Microscope; Electron Microscopy; Endometrial; Epitopes; Equipment; experience; Funding; Histology; Human; Human Resources; Image; Image Analysis; Investigation; Light Microscope; light microscopy; Measurement; MicroRNAs; Microscopy; Molecular Genetics; Mus; new technology; Ovarian; Regulation; Reporter Genes; reproductive; Reproductive Biology; Research; research and development; Research Personnel; Resources; Role; Services; Signal Transduction; Specimen; Systems Biology; tool; Training; Training Support; transcription factor
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5U54HD007495-38_6909 (2011): $147498
A Michael, Professor
University Of Pittsburgh At Pittsburghcity: Pittsburgh country: United States (us)
Abstract: The goals of the Administrative Core are to provide administrative support and structure for the multi-project grant program projects. Specifically, the Administrative Core will 1) provide administrative oversight for the scientific conduct of each of the projects, ensuring that overlap does not occur in the individual projects; 2) provide administrative oversight related to the budgetary interactions between the University of Pittsburgh, Rutgers University and Millenia Hope Inc.; 3) interact with NIH program staff relating to the goals of this U19 multi-project cooperative grant program for the preclinical development of ribonuclease H inhibitors; 4) plan, schedule and coordinate the annual meeting of the Scientific Steering Committee comprised of key personnel from the program project grant, Scientific Advisory Panel members, and NIAID/NIMH Scientific Coordinators; and 5) plan, schedule and conduct monthly teleconferences among the Project Leaders and key personnel
Keywords: Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; AIDS Virus; Applications Grants; Biological Factors; Development; Endoribonuclease H; Endoribonuclease H (Calf Thymus); Ensure; Factor, Biologic; Goals; Grant; Grant Proposals; Grants, Applications; HIV; HTLV-III; Human Immunodeficiency Viruses; Human Resources; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Individual; inhibitor; inhibitor/antagonist; Laboratories; LAV-HTLV-III; Lymphadenopathy-Associated Virus; Manpower; meetings; member; National Institute of Allergy and Infectious Disease; National Institute of Mental Health; National Institute of Mental Health (U.S.); National Institutes of Health; National Institutes of Health (U.S.); Natural Products; NIAID; NIH; NIMH; P01 Mechanism; P01 Program; personnel; Play; pre-clinical; preclinical; Program Project Grant; Program Research Project Grants; programs; Programs (PT); Programs [Publication Type]; Research Program Projects; Ribonuclease H; Ribonuclease H, Calf Thymus; RNase H; Role; SCHED; Schedule; social role; Structure; Teleconferences; therapeutic target; United States National Institute of Mental Health; United States National Institutes of Health; Universities; Virus-HIV
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
5U19AI073975-05_9001 (2011): $66621
AUTOANTIBODIES AGAINST GLYCOPEPTIDE EPITOPES AS SERUM BIOMARKERS OF CANCER
A Michael, Professor
University Of Nebraska Medical Centercity: Omaha country: United States (us)
Grant 5U01CA128437-05 from National Cancer Institute
Abstract: The goal of this research proposal is to develop unique microarray-based assays to detect autoantibodies to glycopeptide epitopes of glycoproteins, and to evaluate their usefulness as diagnostic biomarkers for early detection of adenocarcinomas derived from different organ sites. We will also examine the expression of tumor associated glycan structures and mucin core proteins, in tissues of patients with early and late cancer. Specific Aim 1. Test the hypothesis that autoantibody responses to tumor associated glycopeptide epitopes are useful as early diagnostic or prognostic markers for cancer. We will characterize the specificities of auto- antibodies using novel mucin based O-glycopeptide /glycoprotein arrays for screening sera from breast and pancreatic cancer patients,and serial samples of sera taken before diagnosis of cancer from women subsequently developing breast, ovarian, pancreatic and other carcinomas. Specific Aim 2. Document the expression of cancer-associated mucin O-glycopeptide epitopes from early stage breast (including DCIS) and pancreatic cancer to invasive and metastatic disease, and correlate with the presence or absence of autoantibody responses to these epitopes to be analyzed as under Aim 1. Specific Aim 3. Characterize expression of tumor associated glycans and glycosyltransferases in metastatic pancreatic cancer on a series of cases in which we have primary tumor and multiple metastatic sites obtained by rapid autopsy
Keywords: Adenocarcinoma; Antibodies; Autoantibodies; Autopsy; base; Biological Assay; biomarker; Breast; cancer diagnosis; Cancer Patient; Carcinoma; Case Series; Diagnostic; Disease; Early Diagnosis; Epitopes; Glycopeptides; Glycoproteins; glycosyltransferase; Goals; malignant breast neoplasm; Malignant neoplasm of pancreas; Malignant Neoplasms; mucin core protein; Mucins; Noninfiltrating Intraductal Carcinoma; novel; Organ; Ovarian; Pancreas; Patients; Polysaccharides; Primary Neoplasm; Prognostic Marker; Research Proposals; response; Sampling; Screening procedure; Serum; Site; Specificity; Staging; Structure; Testing; Tissues; tumor; Woman
Project start date: 2007-09-21
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-CA-07-020
5U01CA128437-05 (2011): $277966
THE PATHOBIOLOGY OF AIRWAY DISEASE IN ALPHA-1 ANTITRYPSIN DEFICIENCY
A Michael
University Of Miami School Of Medicinecity: Miami country: United States (us)
Grant 5K01HL084675-05 from National Heart, Lung, And Blood Institute
Abstract: The goal of this application is to provide the candidate with mentored, in-depth research training to become an independent investigator. To achieve this goal, the proposal includes a structured career plan for the candidate´s development as a physician-scientist and a research project that focuses on the mechanisms of airway inflammation in alpha-1 antitrypsin deficiency (AATD). The candidate is a new faculty member with strong commitment to AATD related-research. The sponsor and co-sponsor are established investigators in airway biology and the collaborators are established investigators in the field of AATD research. The overall goal of the research project is to understand the pathogenesis of airway inflammation and chronic bronchitis in AATD, a condition significantly associated with the worst quality of life and more severe airway disease exacerbations in these subjects. Our preliminary studies show that serous cells in the normal airway epithelium and airway submucosal glands (SMG) secrete significant amounts of alpha-1 antitrypsin (AAT). The central hypothesis of the research project is that airway inflammation in AATD is due to a) the loss of AAT activity (from local and systemic origin), b) the extracellular presence of modified AAT molecules that act as chemoattractants in the airway lumen, and c) dysfunction of serous cells, a consequence of accumulating mutant AAT in the endbplasmic reticulum (ER). The aims will test these mechanisms using human airway epithelial cells cultured at the air-liquid interface (ALI) and SMG cell cultures from normal subjects as well as bronchial cells from patients with AATD. Specific Aim 1 will test if loss of AAT activity increases the susceptibility of normal airway epithelial cells to elastase-induced mucin and IL-8 production by testing the effects of adding to ALI cultures basolaterally ("systemic") AAT and suppressing endogenous (local) AAT in SMG cells with the use of siRNA. Specific Aim 2 will investigate the pro-inflammatory effects of AAT polymers and C-36 peptide (AAT degradation product) addition to the apical side of normal ALI cultures on neutrophil migration (and activation) across the airway epithelium by measuring neutrophil transepithelial migration and subsequent epithelial induction of mucin and IL-8 production. In addition, in this Aim we will assess if AAT polymers and C-36 peptides are present in inflamed airways. Specific Aim 3 will test if intracellular accumulation of mutant AAT in airway serous cells leads to ER stress, induction of IL-8, release of AAT polymers and serous cell apoptosis with loss of serous cell function by using Calu-3 cells transfected with mutant AAT and epithelial cells obtained bronchoscopically from AATD patients. Relevance Collectively, these studies will help improve our understanding of the physiologic mechanisms of airway inflammation in AATD and provide insight on the role of local airway AAT production, while providing with the appropriate expertise to begin a productive career as an independent investigator
Keywords: Air; airway epithelium; airway inflammation; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Apical; Apoptosis; Biology; career; Cell Culture Techniques; Cell physiology; Cells; Chemotactic Factors; Chronic Bronchitis; clinical application; Development; Disease; Elastases; Epithelial; Epithelial Cells; Epithelium; extracellular; Faculty; Functional disorder; Genes; Gland; Goals; Green Fluorescent Proteins; Heating; Human; IL8 gene; improved; Individual; Inflammation; Inflammatory; insight; Label; Lactoferrin; Lead; Liquid substance; Measures; member; Mentors; migration; Modeling; MUC5AC gene; Mucins; Mucous body substance; Muramidase; mutant; neutrophil; oncostatin M; Pathogenesis; Patients; Peptides; Peroxidases; Phenotype; Physicians; Physiological; Polymers; Predisposition; Production; Protease Inhibitor; Proteins; Quality of life; Research; Research Personnel; Research Project Grants; research study; Research Training; response; Reticulum; Role; Scientist; Serous; Side; SLPI gene; Small Interfering RNA; Stress; Structure; Testing; Thapsigargin; Tunicamycin
Project start date: 2006-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2012
PFA/PA: RFA-HL-05-015
5K01HL084675-05 (2010): $132597
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