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: 8908020
• 负责人: Kelly A Birdwell
• 金额: $ 6.43万
• 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 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8908020
• 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 study; 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; 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 investigation; clinical practice; cohort; design; diabetes risk; experience; genetic association; genetic epidemiology; genetic variant; genome-wide; genome-wide analysis; glucose metabolism; improved; insulin secretion; insulin sensitivity; loss of function; member; metabolic abnormality assessment; mortality; neurotoxicity; novel; patient oriented research; personalized medicine; 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.

项目摘要/摘要 K23申请的目的是将自己发展成成功的独立研究者进行 以患者为导向的移植药物基因组学研究。作为移植肾脏科医生和教职员工 在范德比尔特大学（Vanderbilt University），我的背景包括以患者为导向研究的高级学位（硕士 临床研究的科学，MSCI）和肾脏病和肾脏移植的正式临床培训。我的 K23应用程序通过结构化的指导程序和教学课程在此背景下建立 提供药理学，遗传学和遗传流行病学，生物统计学和临床​​研究的交叉训练 实现我的直接和长期目标。我的五年目标是成为移植专家 药物基因组学的重点是影响克莫司差异的基本遗传因素 性格和毒性，特别是与异常葡萄糖代谢和新发作糖尿病有关 移植（NODAT）。我的长期目标是成为能够进行的独立医师科学家 大型面向患者的研究和临床试验，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壁外资金，我需要继续 强有力的指导。在此提案中，我们描述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）组和药物基因组学的指导 研究网络（PGRN）以及范德比尔特（Vanderbilt）的合作环境，以提供全面的 指导的教育和研究经验。我的CTSA导师T. Alp Ikizler博士是国际 公认的肾脏疾病代谢并发症的领导者和患者方法论的专家 基于临床研究，担任MSCI计划主任和科学评论主席 CTSA委员会，在培训年轻调查人员方面取得了杰出的成功。我的PGRN导师Dan博士 罗登（Roden）是范德比尔特（Vanderbilt）的个性化医学倡议，是世界知名的专家和先驱 药物基因组学和个性化医学通过他在威胁生命的心律不齐方面的工作。 研究项目将我的精力重点放在对影响对反应的遗传因素的研究上 他克莫司，是肾移植受者中使用最广泛的免疫抑制剂药物。患者 每天需要药物以防止被拒绝移植的器官，但治疗狭窄使其复杂 治疗指数，需要治疗药物监测，高个体间变异性和相关性 毒性。毒性包括增加高血糖的风险和移植后新发作糖尿病的风险 （nodat）。这些条件在临床上很重要，因为它们是增加的危险因素 肾脏移植患者的心血管疾病，这是患有患者的第一名死亡原因 功能移植。我们将检验以下假设：ADME中频繁的多态性（吸收， 分布，代谢和/或消除）和非ADME基因赋予异常葡萄糖的风险增加 用他克莫司治疗的肾脏移植接受者中的体内平衡。指导，职业发展以及 研究计划为了最大化我以简洁的方式检验这一假设的能力，并提供 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者进行遗传关联研究 基因接近。 AIM 1将识别肾脏中与异常葡萄糖代谢相关的遗传变异 使用Vanderbilt的DNA生物库，Biovu及其衬里的去识别电子的移植接受者 全基因组研究中的病历。 AIM 2将使用相同的资源来查找基因变体是否 与肾移植受者中葡萄糖代谢异常相关的与他克莫司有关 药代动力学。 AIM 3将表征与他克莫司有关的候选基因之间的关系 具有胰岛素分泌，胰岛素敏感性，脂肪因子和炎症标记的性格和/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。这将使我能够为未来有效竞争 NIH支持并推动我从事以患者为导向的研究的独立职业。