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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

基本信息

批准号：
9262046
负责人：
Kelly A Birdwell
金额：
$ 12.41万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-20 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262046
关键词：
Pharmacogenomics Tacrolimus New Onset Diabetes

项目摘要

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.

项目摘要/摘要申请K23的目的是将自己发展成为一名成功的独立调查员以患者为中心的移植药物基因组学研究。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中心的研究高级学位(硕士临床研究科学，MSCI)和肾脏内科和肾脏移植的正规临床培训。我的 K23应用程序通过结构化的指导计划和授课课程在此背景下构建提供药理学、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移植专家药物基因组学专注于影响他克莫司个体变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的糖尿病有关的移植(NODAT)。我的长期目标是成为一名独立的内科科学家，能够进行以患者为中心的大型研究和临床试验将个性化医学带入临床实践移植人口。要成功过渡到独立的外部资金，我需要继续强大的指导性。在这份提案中，我们勾勒出了一个受益于DUAL的培训和研究计划通过临床和翻译科学奖(CTSA)小组和药物基因组学进行指导研究网络(PGRN)，以及范德比尔特的协作环境，提供全面的有指导的教育和研究经验。我的CTSA导师T.ALP Ikizler博士是一位国际专家肾脏疾病代谢并发症的公认领导者和患者方法学方面的专家- 以临床研究为基础，担任MSCI项目主任和《科学评论》主席在培训年轻调查人员方面取得了巨大成功。我的PGRN导师丹博士 Roden，作为世界知名的专家和先驱领导Vanderbilt的个性化药物计划通过他在危及生命的心律失常方面的工作，他获得了药物基因组学和个性化药物。本研究项目致力于研究影响人类免疫应答的遗传因素。他克莫司，肾移植受者最广泛使用的免疫抑制药物。病人每天都需要药物来防止移植器官的排斥反应，但治疗因其狭窄而变得复杂治疗指数、治疗药物监测需求、个体间高度变异性以及相关毒物。毒副作用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，因为它们是高血压的独立危险因素。肾移植患者的心血管疾病，这是肾移植患者死亡的头号原因功能正常的移植。我们将检验这样的假设：ADME(吸收，分布、代谢和/或消除)和非ADME基因增加患异常血糖的风险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符合我以简明的方式最大限度地检验这一假设的能力，并提供未来调查的框架。为了验证我们的假设，我们将使用全基因组和候选基因进行遗传关联研究基因接近。目标1将确定与肾脏糖代谢异常相关的遗传变异使用Vanderbilt的DNA生物库BioVU及其在线识别电子设备对他克莫司进行移植的受者全基因组研究中的医疗记录。目标2将使用相同的资源来找出基因变异肾移植受者糖代谢异常与他克莫司有关药物动力学。目标3将描述与他克莫司有关的候选基因之间的关系胰岛素分泌、胰岛素敏感性、脂肪因子和炎症标志物的处置和/或作用前瞻性研究。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、进行和分析药物基因组学研究。这将使我能够在未来有效地竞争 NIH支持并推动我在以患者为中心的研究领域取得了独立的事业。