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.
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.
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