Transcriptional Coregulators in Pancreas Development

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DESCRIPTION (provided by applicant): Failure of insulin secreting pancreatic islet ¿ cells is a hallmark of both type1 and type 2 diabetes, leading to this laboratory's intense focus on molecular mechanisms regulating pancreatic ¿ cell development and function. We previously identified Pcif1 in a yeast two hybrid screen for partners of Pdx1, a homeodomain transcription factor and human diabetes gene pivotally positioned in the transcriptional hierarchy governing the development of ¿ cell mass, the function and survival of adult ¿ cells, and the ability of adult ¿ cells to compensate for increased metabolic demand imposed by insulin resistance. During the previous funding period we determined that Pcif1 acts at least in part through its role as a substrate adaptor to recruit Pdx1 into a cullin3-based complex for ubiquitination and proteasomal degradation, thereby implicating Pcif1 as a target for regulating Pdx1 levels. Indeed, Pcif1 loss of function in ¿ cells elevates Pdx1 protein and stimulates expression of important Pdx1 transcriptional targets, including insulin, MafA and Glut2. In vivo genetic disruption of Pcif1 reveals roles in regulating adult ¿ cell turnover and function and in endocrine lineage allocation during embryonic development, through Pdx1-dependent and, likely, Pdx1-independent mechanisms. We hypothesize that Pcif1 critically regulates embryonic ¿ cell formation and the adult ¿ cell cycle through its ability to modulate the levels/functions of key transcriptional regulators. This hypothesis will be tested in two aims: Aim 1. To determine how Pcif1 regulates the turnover of adult ¿ cells, and Aim 2. To determine how Pcif1 influences the emergence of the ¿ cell lineage during embryonic pancreas development. Insights gained from the proposed experiments will provide a conceptual scaffold for the development of targeted therapeutics that interfere with Pcif1 expression or its interactions with critical substrates in the ¿ cell to influence ¿ cell mass and ¿ cell function, with potential application to approaches involving stem cell differentiation to ¿ cells, cellular reprogramming of ¿ cells from other mature cell types, and for approaches to promote the function and regeneration of endogenous beta cell mass in patients with diabetes. PUBLIC HEALTH RELEVANCE: Failure of insulin secreting pancreatic islet ¿ cells is a hallmark of both type1 and type 2 diabetes, prompting intense effort to develop new sources of insulin- producing ¿ cells for replacement therapies and new ways to promote endogenous ¿ cell regeneration. The proposed studies will address important questions about the functions of the ubiquitin ligase substrate adaptor Pcif1 in ¿ cell biology. Insights gained will provide a conceptual scaffold for the development of targeted therapeutics that interfere with Pcif1 expression or its interactions with critical substrates in the ¿ cell to influence ¿ cell mass and ¿ cell function, with potential application to stem cell differentiation, cellular reprogramming and approaches to promote the function and regeneration of endogenous ¿ cell mass in patients with diabetes.