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: 8721975
• 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/8721975
• 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; 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/摘要 K23申请的目的是将自己发展成为一名成功的独立调查员， 移植药物基因组学中以患者为导向的研究。作为一名移植肾病学家和 在范德比尔特大学，我的背景包括以病人为导向的研究的高级学位（ 临床研究科学，MSCI）和肾脏病学和肾移植的正式临床培训。我 K23应用程序通过结构化的指导计划和教学课程建立在这一背景下， 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方面的交叉培训 来实现我的近期和长期目标我的五年目标是成为器官移植专家 药物基因组学关注影响他克莫司个体差异的潜在遗传因素 处置和毒性，特别是与糖代谢异常和新发糖尿病有关， 移植（NODAT）。我的长期目标是成为一名独立的医生科学家， 以患者为导向的大型研究和临床试验，将个性化医疗纳入临床实践， 移植人口。为了成功过渡到独立的校外资助，我需要继续 强大的指导。在这份提案中，我们描绘了一个培训和研究计划，从双重受益。 通过临床和转化科学奖（CTSA）组和药物基因组学指导 研究网络（PGRN），以及范德比尔特的合作环境，提供全面的 指导教育和研究经验。我的CTSA导师T博士Alp Ikizler是一家国际性的 公认的肾脏疾病代谢并发症的领导者和患者方法学的专家， 基于临床研究，担任MSCI项目主任和科学评论主席 委员会的CTSA，在培训年轻的调查人员取得了杰出的成就。我的PGRN导师丹博士 罗登，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， 通过他在危及生命的心律失常方面的工作，药物基因组学和个性化医疗。 该研究项目的重点是我的努力调查遗传因素，影响反应， 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 需要每天服用这种药物来防止移植器官的排斥反应，但由于其狭窄的治疗范围， 治疗指数、治疗药物监测需求、个体间变异性高，以及相关的 毒性毒性包括移植后高血糖和新发糖尿病的风险增加 （NODAT）。这些情况在临床上很重要，因为它们是增加的独立风险因素。 肾移植患者的心血管疾病，这是患者死亡的头号原因， 功能性移植我们将检验ADME（吸收， 分布、代谢和/或消除）和非ADME基因导致血糖异常风险增加 他克莫司治疗肾移植受者的体内平衡。指导、职业发展和 研究计划吻合，以最大限度地提高我的能力，以简洁的方式测试这一假设，并提供一个 未来调查的框架。 为了验证我们的假设，我们将使用全基因组和候选基因组进行遗传关联研究。 基因方法目的1将确定与肾脏糖代谢异常相关的遗传变异 使用范德比尔特的DNA生物库BioVU及其内衬的去识别电子 一项全基因组研究中的医疗记录。Aim 2将使用相同的资源来发现基因变异是否 与肾移植受者糖代谢异常相关的药物与他克莫司有关 药代动力学目标3将描述与他克莫司有关的候选基因之间的关系 与胰岛素分泌、胰岛素敏感性、脂肪因子和炎症标志物的关系， 前瞻性研究在完成拟议的培训和研究计划时，我将获得必要的专业知识， 设计、实施和分析药物基因组学研究。这将使我能够有效地竞争， NIH支持并推动我在以患者为导向的研究中独立工作。