Investigation of noncoding variation in human pancreatic islets and their develop

人胰岛非编码变异及其相关基因的研究 发育前体。 这项研究项目的目标是了解遗传变异在非传染性疾病中的作用。 人类胰岛功能中的蛋白质编码、基因组调控区和 功能障碍。胰岛中的胰岛素分泌细胞负责维持正常 血糖水平。2型糖尿病(T2D)是由这些疾病的进行性衰竭引起的 细胞在血糖水平升高的情况下分泌胰岛素，是导致 美国和全世界的发病率和死亡率都很高。发展 T2D涉及个体基因和环境之间复杂的相互作用。 遗传关联研究已经确定了基因组中大约40个区域 增加了发展T2D的风险。这些区域中的大多数都不包含编码 序列变体，但包含非编码变体。这个项目使用基因组- 广泛的染色质图谱，以确定有助于 T2D通过确定哪些候选调控区域起到增强子的作用， 人类胰岛中的消音器或绝缘体(具体目标1)以及哪些元素包含 改变成人胰岛(特异性目标2)或胰腺中基因表达的变体 前体细胞(特定目标3)。完成这些目标将提供详细的 增强器、消音器和绝缘体元件的功能注释，标识键 调控元件-启动子相互作用，并确定T2D相关和其他 变异体在人类胰腺前体细胞或成熟胰岛细胞中改变其功能。

Title: Investigation of noncoding variation in human pancreatic islets and their developmental precursors. The goal of this research project is to understand the role of genetic variation in non- protein coding, regulatory regions of the genome in human pancreatic islet function and dysfunction. Insulin-secreting cells in the islet are responsible for maintaining normal blood glucose levels. Type 2 diabetes (T2D) results from progressive failure of these cells to secrete insulin in the face of increasing blood glucose levels and is the cause of substantial morbidity and mortality in the United States and worldwide. Development of T2D involves complex interactions between an individual's genes and environment. Genetic association studies have identified approximately 40 regions in the genome that confer risk of developing T2D. The majority of these regions does not contain coding sequence variants, but instead contains non-coding variants. This project uses genome- wide chromatin profiling to identify the critical regulatory elements that contribute to T2D by determining which of the candidate regulatory regions function as enhancers, silencers, or insulators in human islets (Specific Aim 1) and which elements contain variants that alter gene expression in adult human islets (Specific Aim 2) or in pancreatic precursor cells (Specific Aim 3). Completion of these aims will provide detailed functional annotation of enhancer, silencer, and insulator elements, identify key regulatory element-promoter interactions, and identify how T2D-associated and other variants alter their function in human pancreatic precursor or mature islet cells.