Genetic Epidemiology and Renal Allograft Outcomes

申请人简介(申请人提供)：申请人为肾脏病研究员，受过遗传学和临床流行病学方面的高级培训，长期对临床研究感兴趣。这项申请提出了一个全面的，跨学科的计划，将为申请人提供必要的技能和经验，他的发展成为一名独立的研究人员，肾脏，遗传流行病学。这个有指导的培训方案的主要目标是获得必要的技能，以成为一名独立的临床调查员和解决肾移植重要问题的遗传流行病学家。该计划的培训部分包括宾夕法尼亚大学临床流行病学主任哈罗德·I·费尔德曼博士的指导工作，以及完成正规课程工作和获得流行病学博士学位的论文。研究部分的目的是确定与原发性高血压的发展相关的基因的等位基因变异是否也与移植肾的存活有关。高血压对移植肾的存活有实质性的负面影响。与原发性高血压相关的几个基因在免疫反应、生长因子和纤维化的调节中也发挥着重要作用。了解移植肾存活的潜在决定因素的遗传变异可能有助于扩大移植肾功能的治疗。这项研究的目的将通过在特拉华河谷接受肾移植的成人患者中进行的一项多中心前瞻性队列研究来实现。通过对同种异体移植受者的DNA样本进行聚合酶链式反应，将确定以下基因的遗传多态性：血管紧张素转换酶、血管紧张素原、血管紧张素Ⅱ1型受体、醛固酮合成酶和Gi-蛋白β-3亚单位基因。这些基因的选择是基于似是而非、潜在的原因、发生频率和以前在相关环境中发表的验证研究。将采用COX比例风险模型来探索候选基因多态与同种异体移植物丢失时间的关系。通过识别影响同种异体移植物存活的基因多态，这项研究将有助于识别有风险的患者，并将有助于开发针对关键途径的治疗方法。

DESCRIPTION (provided by applicant):The applicant is a nephrology fellow with advanced training in genetics and clinical epidemiology and a longstanding interest in clinical research. This application proposes a comprehensive, interdisciplinary program that will provide the applicant with the skills and experience necessary for his development into an independent investigator in renal, genetic epidemiology. The principal objective of this mentored training proposal is to acquire the necessary skills to become an independent clinical investigator and a genetic epidemiologist addressing important issues in renal transplantation. The training component of this program includes a preceptorship with Dr. Harold I. Feldman, Chief of Clinical Epidemiology, University of Pennsylvania and completion of the formal course work and dissertation leading to a Ph.D. degree in Epidemiology. The objective of the research component is to determine whether allelic variants of genes that are associated with development of essential hypertension are also associated with renal allograft survival.Hypertension has a substantial negative impact on renal allograft survival. Several genes that are associated with essential hypertension also play an important role in the modulation of immune response, growth factors and fibrosis. Understanding genetic variants of potential determinants of renal allograft survival may allow for treatments that extend the function of kidney allografts. The research aims will be acomplished via a multicenter, prospective cohort study among adult recipients of renal allografts in the Delaware Valley. The genetic polymorphisms of the following genes will be determined by PCR of DNA samples from the allograft recipients: angiotensin-converting enzyme, angiotensinogen, angiotensin II Type 1 receptor, aldosterone synthase and the Gi-protein Beta-3 subunit gene. The selection of these genes is based on plausibility, potential causation, frequency of occurrence and previously published validation studies in related settings. A Cox proportional hazard model will be implemented to explore the relationship of the candidate gene polymorphisms with time to allograft loss. By identifying genetic polymorphisms that impact allograft survival, this study will help identify patients at risk and will help in the development of therapies targeting critical pathways.