ATF5 in the developing pancreas and survival functions in the mature beta cell.

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DESCRIPTION (provided by applicant): Proper function, development, and survival of the pancreatic insulin secreting ?-cell is critical for the prevention of diabetes. Thus mediators of these functions are highly important in the understanding of diabetes development and for discovery of feasible therapies. Activating transcription factor 5 (ATF5) is a transcription factor that has demonstrated anti-apoptotic, pro-survival, and differentiation roles in olfactory sensory neurons, hematopoietic cells, and several cancers. Preliminary data indicate that ATF5 is expressed during embryonic pancreatic development, in mature ?-cells, and enriched in pancreatic islets. However, the role of ATF5 in the developing and mature pancreas is not known. Aim 1 of this proposal will determine the role of ATF5 in pancreatic development through morphological and gene expression analysis of the pancreas and islets of an available global Atf5-/- mouse compared to WT littermates throughout gestational development. Results will delineate the specific targets important for ATF5 in the development of the pancreas, endocrine compartment, and islet architecture. Preliminary data indicate that ATF5 is a direct target of regulation by PDX1 in the mature ? -cell. PDX1 is known to have pro-survival roles pertaining to ER stress susceptibility in the mature ? -cell. Aim 2 of this proposal will focus on the mediation of PDX1 pro-survival roles and targets regulated by ATF5 in the mature ? -cell in the context of stress stimuli (e.g. nutrient deprivation, oxidative stress, ER stress) known to be detrimental to the ?-cell. Rescue of phenotypes resulting from PDX1 deficiency by overexpression of ATF5 in mature ?-cells will reveal the role of ATF5 in PDX1 signaling pathways and pro- survival functions. ATF5 will be further characterized by immunofluorescent staining, immunoprecipitation, fractionation, and mass spectrometry to reveal previously unknown binding partners, subcellular localization within the cell, and mechanisms of activation. This proposal is important as a point of discovery for a new set of targets for manipulation of ? -cell survival in the context of deleterious stimuli as well as possible preventive therapies for diabetes.