Pharmacogenomics of Tacrolimus and New Onset Diabetes After Kidney Transplant

他克莫司的药物基因组学与肾移植后新发糖尿病

• 批准号: 8539384
• 负责人: Kelly A Birdwell
• 金额: $ 18.85万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539384
• 关键词: Adverse effects; Affect; Arrhythmia; Award; Biometry; Blood; CYP3A5 gene; Calcineurin Pathway; Calcineurin inhibitor; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Chronic; Clinical; Clinical Research; Clinical Sciences; Clinical Trials; Clinical and Translational Science Awards; Complement; Computerized Medical Record; Cyclosporine; DNA; DNA Databases; Databases; Development; Diabetes Mellitus; Dialysis procedure; Disease; Dose; Drug Kinetics; Drug Monitoring; End stage renal failure; Environment; Event; Extramural Activities; Faculty; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Glucose; Goals; Graft Rejection; Graft Survival; Human Genetics; Hyperglycemia; Hypertension; Immunosuppressive Agents; Individual; Inflammation; Insulin; Insulin Resistance; Interleukin-10; Interleukin-6; Investigation; Kidney Diseases; Kidney Transplantation; Knowledge; Leptin; Life; Link; Master of Science; Measures; Medicine; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Methodology; Modification; Nephrology; Non-Insulin-Dependent Diabetes Mellitus; Organ Transplantation; Outcome; Pancreas; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Physicians; Population; Positioning Attribute; Prospective Studies; Quality of life; Regimen; Research; Research Personnel; Research Project Grants; Research Training; Resources; Review Committee; Risk; Risk Factors; Scientist; Site; Structure; TCF7L2 gene; Tacrolimus; Testing; Therapeutic; Therapeutic Index; Toxic effect; Training; Translational Research; Transplant Recipients; Transplantation; United States; United States National Institutes of Health; Universities; Variant; Work; absorption; abstracting; adipokines; adiponectin; base; biobank; blood glucose regulation; cardiovascular risk factor; career; career development; clinical practice; cohort; design; diabetes risk; experience; genetic association; genetic epidemiology; genetic variant; genome wide association study; genome-wide; glucose metabolism; improved; insulin secretion; insulin sensitivity; loss of function; member; metabolic abnormality assessment; mortality; neurotoxicity; novel; patient oriented research; prevent; programs; prospective; research and development; research study; response; success

Project Summary/Abstract The purpose of the K23 application is to develop myself into a successful independent investigator conducting patient-oriented research in transplant pharmacogenomics. As a transplant nephrologist and faculty member of at Vanderbilt University, my background includes an advanced degree in patient-oriented research (Master of Science in Clinical Investigation, MSCI) and formal clinical training in nephrology and kidney transplant. My K23 application builds on this background through a structured mentored program and didactic coursework to provide cross-training in pharmacology, genetics and genetic epidemiology, biostatistics, and clinical research to achieve my immediate and long-term goals. My five-year goal is to become an expert in transplant pharmacogenomics focused on the underlying genetic factors that affect individual variation in tacrolimus disposition and toxicities, particularly in relation to abnormal glucose metabolism and new onset diabetes after transplant (NODAT). My long-term goal is to become an independent physician scientist capable of conducting large patient-oriented research studies and clinical trials to bring personalized medicine into clinical practice in the transplant population. To successfully transition to independent extramural funding, I require continued strong mentorship. In this proposal, we delineate a training and research plan that benefits from dual mentorship through the Clinical and Translational Science Award (CTSA) group and the Pharmacogenomics Research Network (PGRN), as well as the collaborative milieu of Vanderbilt, to provide a comprehensive mentored educational and research experience. My CTSA mentor, Dr. T. Alp Ikizler, is an internationally recognized leader on the metabolic complications of kidney disease and expert in the methodology of patient- based clinical research, serving as the director of the MSCI program and chair of the Scientific Review Committee for the CTSA, with outstanding success in training young investigators. My PGRN mentor, Dr. Dan Roden, leads Vanderbilt's personalized medicine initiative as a world-renowned expert and pioneer in pharmacogenomics and personalized medicine through his work in life-threatening arrhythmias. The research project focuses my efforts on the investigation of genetic factors that affect response to tacrolimus, the most widely used immunosuppressant medication in kidney transplant recipients. Patients require the drug daily to prevent rejection of the transplanted organ, but therapy is complicated by its narrow therapeutic index, need for therapeutic drug monitoring, high inter-individual variability, and associated toxicities. Toxicities include increased risk for hyperglycemia and new onset diabetes after transplant (NODAT). These conditions are clinically important because they are independent risk factors for increased cardiovascular disease in kidney transplant patients, which is the number one cause of death in patients with a functioning transplant. We will test the hypothesis that frequent polymorphisms in ADME (absorption, distribution, metabolism and/or elimination) and non-ADME genes confer increased risk for abnormal glucose homeostasis in kidney transplant recipients treated with tacrolimus. The mentoring, career development, and research plans dovetail to maximize my ability to test this hypothesis in a concise manner and provide a framework for future investigations. To test our hypothesis, we will perform genetic association studies using both genome-wide and candidate gene approaches. Aim 1 will identify genetic variants associated with abnormal glucose metabolism in kidney transplant recipients on tacrolimus using Vanderbilt's DNA biobank, BioVU, and its lined de-identified electronic medical record in a genome-wide study. Aim 2 will use the same resources to find whether gene variants associated with abnormal glucose metabolism in kidney transplant recipients are associated with tacrolimus pharmacokinetics. Aim 3 will characterize relationships between candidate genes implicated in tacrolimus disposition and/or action with markers of insulin secretion, insulin sensitivity, adipokines, and inflammation in a prospective study. In completing the proposed training and research plans, I will gain the necessary expertise to design, conduct, and analyze pharmacogenomics studies. This will allow me to compete effectively for future NIH support and propel me to an independent career in patient-oriented research.

项目总结/文摘