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一个成功的独立研究者，该研究人员从事以患者为导向的移植药物基因组学研究。作为范德比尔特大学（Vanderbilt University）的移植肾脏科医生和教职员工，我的背景包括以患者为导向的研究高级学位（临床研究硕士，MSCI）和肾脏病和肾脏移植的正式临床培训。我的K23应用程序是通过结构化的指导计划和教学课程在此背景下建立的，以提供药理学，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，以实现我的直接和长期目标。我的五年目标是成为移植药物基因组学专家，重点是影响克莫司处置和毒性差异的潜在遗传因素，特别是在移植后（Nodat）后与异常的葡萄糖代谢和新的发作糖尿病有关。我的长期目标是成为一名独立的医师科学家，能够进行大型的以患者为导向的研究和临床试验，以将个性化医学带入移植人群的临床实践。为了成功地过渡到独立的壁外资金，我需要持续强大的指导。在该提案中，我们描述了一个培训和研究计划，该计划通过临床和转化科学奖（CTSA）小组和药物基因组学研究网络（PGRN）以及范德比尔特的协作环境从双重指导中受益，以提供全面的指导教育和研究经验。我的CTSA导师T. Alp Ikizler博士是肾脏疾病代谢并发症的国际认可领导者，也是基于患者的临床研究方法论的专家，是MSCI计划主任，也是CTSA科学审查委员会主席，并在培训年轻调查人员中取得了杰出的成功。我的PGRN导师丹·罗登（Dan Roden）博士领导了范德比尔特（Vanderbilt）的个性化医学倡议，作为世界著名的药物基因组学和个性化医学专家，并通过他的威胁生命的心律不齐的工作。该研究项目将我的精力集中在对影响克莫司反应的遗传因素上，这是对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拒绝移植器官，但治疗狭窄的治疗指数，治疗性药物监测的需求，高个体间可变性以及相关的毒性使其复杂化。毒性包括移植后高血糖的风险增加和新发作糖尿病（NODAT）。这些疾病在临床上很重要，因为它们是肾脏移植患者心血管疾病增加的独立危险因素，这是手术正常的患者死亡原因第一。我们将检验以下假设：ADME（吸收，分布，代谢和/或消除）中频繁的多态性和非ADME基因赋予在用他氨基糖治疗的肾脏移植受者中葡萄糖稳态异常的风险增加。指导，职业发展和研究计划为了最大程度地提高我以简洁的方式检验这一假设的能力，并为未来的研究提供框架。为了检验我们的假设，我们将使用全基因组和候选基因方法进行遗传关联研究。 AIM 1将使用Vanderbilt的DNA生物库，Biovu及其在全基因组的研究中使用vanderbilt的DNA Biobank，Biovu及其衬里的去识别的电子病历来鉴定与他克莫司肾脏移植受者中与异常葡萄糖代谢相关的遗传变异。 AIM 2将使用相同的资源来查找与肾移植受者中与异常葡萄糖代谢相关的基因变异物与他克莫司药代动力学有关。 AIM 3将在一项前瞻性研究中表征与他克莫司处置有关的候选基因和/或作用与胰岛素分泌，胰岛素敏感性，脂肪因子和炎症标记的作用之间的关系。在完成拟议的培训和研究计划时，我将获得设计，进行和分析药物基因组学研究的必要专业知识。这将使我能够有效地争夺未来的NIH支持，并推动我从事以患者为导向的研究的独立职业。 公共卫生相关性：克莫司在肾移植中的毒性是移植后高血糖和新发作糖尿病的发展，临床状况增加了这些患者心血管事件的风险。使用全基因组和候选基因关联研究，我们将研究与他克莫司的肾脏移植患者中与异常葡萄糖代谢相关的遗传因素。这可能会使免疫抑制治疗的修改以降低糖尿病的风险并改善长期移植预后。