Epigenomic Profiling of Normal and Diabetic Pancreatic Beta-Cells

描述（由申请人提供）：糖尿病是一种终身慢性疾病，2007年全球患病率估计为1.8亿。在过去的十年中，人们已经清楚，胰腺细胞的衰竭是导致显性糖尿病转变的最终事件，尽管肥胖和外周胰岛素抵抗是导致糖尿病前期的因素。细胞衰竭在这里被定义为两种功能的丧失，即葡萄糖刺激胰岛素分泌，以及细胞质量不足，要么是由于细胞凋亡增加，要么是由于代谢需求导致细胞增殖失败。虽然有几种药物被用于降低胰岛素抵抗和增加胰岛素分泌，但没有一种药物能解决这个问题

DESCRIPTION (provided by applicant): Diabetes mellitus is a lifelong chronic disease with worldwide prevalence estimated at 180 million patients in 2007. Over the past decade, it has become clear that failure of the pancreatic ¿-cell is the final event causing the transition to overt diabetes, even though obesity and peripheral insulin resistance are the factors leading to pre-diabetes. ¿-cell failure here is defined as loss of both function, i.e. glucose stimulated insulin secretion, and inadequate ¿-cell mass, either by increased apoptosis or a failure to proliferate in response to metabolic demand. While several drugs are in use to reduce insulin resistance and increase insulin secretion, none exist that address ¿-cell failure. In fact, at present, no good targets are known that would allow such drug development. Because the ¿-cell plays such a central role in the pathogenesis of diabetes, and because epigenetic factors (i.e. long term changes in the transcriptional program reflected in chromatin status) are likely to be the predominant consequence of the life-style changes and environmental factors that lead up to diabetes, we will determine the epigenome of both healthy and type 2 diabetic human ¿-cells. This effort will lay the groundwork to defining the pathways and genes that can be targeted in the future for the development of new therapies that address ¿-cell failure. Specifically, we will determine both activating and repressing chromatin marks in ¿-cells isolated from 50 healthy and 50 type 2 diabetic organ donors using ChIP-Seq technology. Secondly, we will analyze the microRNA profile in the same ¿-cell preparations, as miRNAs are strong candidates to modify the transcriptome of the diabetic ¿-cell. Third, we will analyze a novel chromatin mark discovered at Penn that links the stress mediator AMPK to chromatin status. Fourth, we will perform a comprehensive computational biology analysis to identify the nodes and regulatory pathways that are affected in diabetic ¿-cells.