GENETIC INTERACTIONS AND INSULIN SECRETION

作为一名发展中的医生科学家，我的职业目标是培养和整合我作为临床医生和研究者的经验，以便我可以将新的机制见解转化为糖尿病的病理生理学基础。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，重点是参与胰腺发育和胰岛素分泌的基因。本建议书中概述的研究将使我能够申请并扩展我作为临床研究者的培训，并将通过临床研究和遗传学课程的工作来补充。马里兰州大学和约翰霍普金斯湾景医疗中心GCRC提供了一个丰富的合作和支持环境，无论是在机构层面还是在艾伦·舒尔迪纳博士的实验室内。Shuldiner博士和我制定的基于指导的工作和具体的职业发展计划将为我提供作为独立研究职业所需的技能。2型糖尿病是一种多基因异质性疾病，其特征在于存在β细胞功能障碍和胰岛素抵抗。我们推测，参与胰岛素分泌和/或胰腺发育的基因中的常见突变导致胰岛素分泌异常，这反过来又有助于2型糖尿病的发展。此外，我们推测，在一个以上的基因多态性可能对胰岛素分泌有累加效应，并增加发展为2型糖尿病的可能性。已经在已知影响胰岛素分泌和/或胰腺发育的几种基因中鉴定出多态性[例如，胰十二指肠同源盒因子-1（PDX-1）Asp 76 Asn、β 2/NeuroD Ala 45 Thr、胰岛素受体底物-2（IRS-2）Gly 1057 Asp和β 3肾上腺素能受体（β 3AR）Trp 64 Arg]。为了验证我们的假设，我们建议前瞻性招募具有这些多态性的非糖尿病受试者，并使用胰岛素原水平、胰岛素修饰的频繁采样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。在具体目标I中，受试者将具有多态性中的一种和其他三种基因的正常基因型，并且在具体目标2中，受试者将具有多态性中的两种和其他两种基因的正常基因型。通过这些研究和独特的招募方案，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型糖尿病遗传学和病理生理学的新机制理解以及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.