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: 8334466
• 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/8334466
• 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.

项目概要/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，进行 以患者为导向的移植药物基因组学研究。作为移植肾病专家和教员 在范德比尔特大学，我的背景包括以患者为导向的研究高级学位（硕士 临床研究科学 (MSCI) 以及肾病学和肾移植方面的正式临床培训。我的 K23 应用程序建立在这一背景之上，通过结构化的指导计划和教学课程来 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 实现我的近期和长期目标。我的五年目标是成为移植专家 药物基因组学侧重于影响他克莫司个体差异的潜在遗传因素 处置和毒性，特别是与葡萄糖代谢异常和新发糖尿病相关 移植（NODAT）。我的长期目标是成为一名独立的医师科学家，能够进行 大型患者导向的研究和临床试验，将个性化医疗带入临床实践 移植人群。为了成功过渡到独立的外部资助，我需要继续 强有力的指导。在本提案中，我们描绘了一个受益于双重的培训和研究计划 通过临床和转化科学奖 (CTSA) 小组和药物基因组学的指导 研究网络（PGRN）以及范德堡大学的协作环境，提供全面的 指导教育和研究经验。我的 CTSA 导师 T. Alp Ikizler 博士是一位国际 肾脏疾病代谢并发症方面公认的领导者和患者治疗方法方面的专家 基于临床研究，担任 MSCI 项目主任和科学审查主席 CTSA 委员会在培训年轻研究者方面取得了显著成功。我的 PGRN 导师 Dan 博士 罗登（Roden）作为世界知名专家和先驱，领导范德堡大学的个性化医疗计划 通过他对危及生命的心律失常的研究，他在药物基因组学和个性化医疗方面取得了长足的进步。 该研究项目的重点是调查影响反应的遗传因素 他克莫司是肾移植受者中使用最广泛的免疫抑制剂。患者 需要每天使用药物来防止移植器官的排斥，但由于其狭窄，治疗变得复杂 治疗指数、治疗药物监测的需要、个体间的高变异性以及相关的 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危险因素。 肾移植患者的心血管疾病是导致肾移植患者死亡的第一大原因 功能移植。我们将检验 ADME 中频繁多态性（吸收、 分布、代谢和/或消除）和非 ADME 基因会增加异常血糖的风险 用他克莫司治疗的肾移植受者的体内平衡。指导、职业发展和 研究计划相吻合，以最大限度地提高我以简洁的方式检验这一假设的能力，并提供一个 未来调查的框架。 为了检验我们的假设，我们将使用全基因组和候选基因进行遗传关联研究 基因方法。目标 1 将识别与肾脏葡萄糖代谢异常相关的遗传变异 使用范德比尔特 DNA 生物库 BioVU 及其内衬的去识别化电子设备接受他克莫司的移植受者 全基因组研究中的医疗记录。目标2将使用相同的资源来查找基因是否变异 肾移植受者葡萄糖代谢异常与他克莫司有关 药代动力学。目标 3 将描述与他克莫司相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 支持并推动我从事以患者为导向的研究的独立职业。