GENETIC INTERACTIONS AND INSULIN SECRETION

作为一名发展中的内科医生-科学家，我的职业目标是培养和整合我作为临床医生和研究人员的经验，以便我可以将对糖尿病病理生理基础的新机械见解转化到床边。我致力于学术医学的职业生涯，目标是发展糖尿病的临床和科学专业知识，重点是与胰腺发育和胰岛素分泌有关的基因。这项提案中概述的研究将使我能够应用和扩展我作为临床研究人员的培训，并将通过临床调查和遗传学的课程工作来补充。马里兰大学和约翰霍普金斯大学海湾医学中心GCRC为合作和支持提供了丰富的环境，无论是在机构层面还是在Alan Shuldiner博士的实验室内。舒尔迪纳博士和我制定的以指导为基础的工作和具体的职业发展计划将为我提供作为一名独立研究人员出类拔萃所需的技能。2型糖尿病是一种多基因、异质性疾病，以胰岛β细胞功能障碍和胰岛素抵抗为特征。我们假设，与胰岛素分泌和/或胰腺发育相关的常见基因突变会导致胰岛素分泌异常，进而导致2型糖尿病的发生。此外，我们假设存在一个以上基因的多态可能对胰岛素分泌有相加作用，并增加发展为2型糖尿病的可能性。已在几个已知的影响胰岛素分泌和/或胰腺发育的基因[如胰腺十二指肠同源盒因子-1(PDX-1)Asp76Asn、β2/Neurod Ala45Thr、胰岛素受体底物2(IRS-2)Gly1057Asp和β-3肾上腺素能受体(Beta3AR)Trp64Arg]中发现了多态性。为了验证我们的假设，我们建议前瞻性地招募具有这些多态的非糖尿病受试者，并使用胰岛素原水平、胰岛素修饰的频繁静脉葡萄糖耐量试验和胰岛素振荡研究来表征胰岛素分泌。在特定目标1中，受试者将具有其他三个基因的一个多态和正常基因型，而在特定目标2中，受试者将具有另外两个基因的两个多态和一个正常基因型。通过这些研究和独特的招募计划，我们将确定这些多态性在糖尿病多基因模型中的作用，这将导致对2型糖尿病的遗传学和病理生理的新的机制理解和新的预防和治疗策略。

As a developing Physician-Scientist, my career goal is to cultivate and integrate my experiences as a clinician and investigator so that I may translate new mechanistic insights into the pathophysiolgical basis of diabetes to the bedside. I am committed to a career in academic medicine with the goal of developing clinical and scientific expertise in diabetes with a focus on genes involved in pancreatic development and insulin secretion. The studies outlined in this proposal will allow me to apply and extend my training as a clinical investigator and will be complemented by course work in clinical investigation and genetics. The University of Maryland and Johns Hopkins Bayview Medical Center GCRC provide a rich environment for collaboration and support, both at an institutional level and within Dr. Alan Shuldiner's laboratory. The mentored-based work and specific career development plan that Dr. Shuldiner and I have developed will provide me with the skills needed to excel as an independent research career. Type 2 diabetes mellitus is a polygenic, heterogeneous disorder characterized by the presence of beta cell dysfunction and insulin resistance. We hypothesize that common mutations in genes involved in insulin secretion and/or pancreatic development result in abnormal insulin secretion which in turn contribute to the development of type 2 diabetes. Furthermore, we hypothesize that having polymorphisms in more than one gene may have additive effects on insulin secretion and increase the likelihood of developing type 2 diabetes. Polymorphisms have been identified in several genes known to effect insulin secretion and/or pancreatic development [e.g., pancreatic duodenal homeobox factor-1 (PDX-1) Asp76Asn, Beta 2/NeuroD Ala45Thr, insulin receptor substrate-2 (IRS-2) Gly1057Asp, and beta-3adrenergic receptor (beta3AR) Trp64Arg]. To test our hypotheses, we propose to prospectively recruit nondiabetic subjects with these polymorphisms and characterize insulin secretion using proinsulin levels, the insulin- modified frequently sampled intravenous glucose tolerance test and insulin oscillation studies. In specific aim I, subjects will have one of the polymorphisms and a normal genotype for the other three genes, and in specific aim 2, subjects will have two of the polymorphisms, and a normal genotype for the other two genes. Through these studies and unique recruitment scheme, we will determine the role of these polymorphisms in a polygenic model of diabetes that will lead to a new mechanistic understanding of the genetics and pathophysiology of type 2 diabetes and new preventive and therapeutic strategies.