Epigenomics of the regenerating and aging beta-cell

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。在过去的十年里，人们已经很清楚，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细胞扩张和再生问题。事实上，目前还没有发现可以开发这种药物的良好靶点。在人类和啮齿类动物中，随着年龄的增长，细胞的增殖潜力急剧下降。这种变化背后的表观遗传事件只得到了部分探索。我们假设，充分了解与细胞再生能力相关的表观遗传变化可以用来使衰老细胞增殖。

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 expansion and regeneration. In fact, at present, no good targets are known that would allow such drug development. There is a dramatic decline in the proliferative potential of the (-cell with age, both in humans and in rodents. The epigenetic events that underlie this change have been only partially explored. We hypothesize that a full understanding of the epigenetic changes that correlate with the regenerative capacity of the (-cell can be utilized to enable aged (-cells to proliferate. Specifically, we will determine both activating and repressing chromatin marks as well as expression profiles of (-cells isolated from young and aged mice by ultra-high throughput sequencing technology. We will also investigate the epigenetic changes that occur when a recently divided (-cell enters a refractory period. Secondly, we utilize the epigenetic profile of the young (-cell obtained in AIM 1 in a low-throughput screen of conditions aimed at reversing the aged phenotype of human (-cells. Third, we will evaluate the ubiquitin ligase adaptor PCIF1, shown to be an important regulator of the chromatin modifier BMI1, as a target for reversal of the epigenetic phenotype of the aged human (-cell. In summary, we will utilize genome-wide approaches and computational biology tools to transform our knowledge of how the epigenome reflects the aging of the (-cell and its loss of proliferative potential. These data will serve two purposes: to guide the development of interventions that aim to rejuvenate human islets, and to evaluate how their epigenome can be manipulated to favor (-cell replication. Therefore, our proposal has the potential to transform diabetes research and treatment in the future. PUBLIC HEALTH RELEVANCE: Health outcomes for both type I and type II diabetics could be improved if we could develop drugs to stimulate the proliferation of the beta-cell, the insulin producing cell in the pancreas. Likewise, more type I diabetics could be treated with islet transplantation if we could expand beta-cell mass in vitro before transplantation. While beta-cells in young children have very high proliferative capacity, this declines dramatically as we age. We hypothesize that epigenetic changes are responsible for this decline in proliferative capacity. Therefore, we will determine the epigenome of both young and aged beta-cells, define their differences, and use these as a tool to investigate treatments that can reverse the aged phenotype of the human beta-cell. If successful, this novel approach holds great promise for the development of innovative treatments for diabetes.