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: 8226376
• 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/8226376
• 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; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: A toxicity of tacrolimus in kidney transplantation is the development of hyperglycemia and new onset diabetes after transplant, clinical conditions which increase the risk of cardiovascular events in these patients. Using genome-wide and candidate gene association studies, we will study the genetic factors associated with abnormal glucose metabolism in kidney transplant patients taking tacrolimus. This may allow modification of immunosuppressive treatment to decrease risk of diabetes and improve long term transplant outcomes.

描述（由申请人提供）：K23申请的目的是将自己发展成为一名成功的独立研究者，在移植药物基因组学领域开展以患者为导向的研究。作为范德比尔特大学的移植肾病学家和教员，我的背景包括以患者为导向的研究的高级学位（临床研究理学硕士，MSCI）和肾脏病学和肾移植的正式临床培训。我的K23应用程序通过结构化的辅导计划和教学课程建立在这个背景上，提供药理学，遗传学和遗传流行病学，生物统计学和临床研究的交叉培训，以实现我的近期和长期目标。我的五年目标是成为移植药物基因组学专家，专注于影响他克莫司处置和毒性个体差异的潜在遗传因素，特别是与糖代谢异常和移植后新发糖尿病（NODAT）有关。我的长期目标是成为一名独立的医生科学家，能够进行大型的以患者为导向的研究和临床试验，将个性化医疗纳入移植人群的临床实践。为了成功地过渡到独立的校外资金，我需要持续强大的指导。在本提案中，我们描述了一个培训和研究计划，通过临床和转化科学奖（CTSA）组和药物基因组学研究网络（PGRN）以及范德比尔特的合作环境，从双重导师制中受益，以提供全面的指导教育和研究经验。我的CTSA导师T博士Alp Ikizler是国际公认的肾脏疾病代谢并发症的领导者和基于患者的临床研究方法学专家，担任MSCI项目主任和CTSA科学审查委员会主席，在培训年轻研究人员方面取得了杰出的成功。我的PGRN导师，丹罗登博士，领导范德比尔特的个性化医疗倡议作为一个世界知名的专家和先驱，在药物基因组学和个性化医疗通过他的工作在危及生命的心律失常。该研究项目的重点是调查影响他克莫司反应的遗传因素，他克莫司是肾移植受者中最广泛使用的免疫抑制剂药物。患者每天需要药物来防止移植器官的排斥反应，但治疗因其狭窄的治疗指数、需要治疗药物监测、高个体间变异性和相关毒性而变得复杂。毒性包括高血糖和移植后新发糖尿病（NODAT）的风险增加。这些情况在临床上很重要，因为它们是肾移植患者心血管疾病增加的独立风险因素，这是功能正常的移植患者死亡的头号原因。我们将检验ADME（吸收、分布、代谢和/或消除）和非ADME基因的频繁多态性增加接受他克莫司治疗的肾移植受者葡萄糖稳态异常风险的假设。指导，职业发展和研究计划相吻合，以最大限度地提高我的能力，以简洁的方式测试这一假设，并为未来的调查提供一个框架。为了验证我们的假设，我们将使用全基因组和候选基因方法进行遗传关联研究。目的1将在全基因组研究中，使用范德比尔特的DNA生物库BioVU及其去识别化电子病历，识别与他克莫司肾移植受者糖代谢异常相关的遗传变异。目标2将使用相同的资源，以发现是否与肾移植受者的异常糖代谢相关的基因变异与他克莫司的药代动力学。目的3将在一项前瞻性研究中描述与他克莫司处置和/或作用有关的候选基因与胰岛素分泌、胰岛素敏感性、脂肪因子和炎症标志物之间的关系。在完成拟议的培训和研究计划，我将获得必要的专业知识，设计，进行和分析药物基因组学研究。这将使我能够有效地竞争未来的NIH支持，并推动我在以患者为导向的研究中独立的职业生涯。 公共卫生关系：他克莫司在肾移植中的毒性是移植后高血糖症和新发糖尿病的发展，这些临床状况增加了这些患者心血管事件的风险。利用全基因组和候选基因关联研究，我们将研究与肾移植患者服用他克莫司时糖代谢异常相关的遗传因素。这可能允许修改免疫抑制治疗以降低糖尿病风险并改善长期移植结果。