NeuroD function during Beta cell development and in mouse models of diabetes

Columbia University Health Sciences, New York NY

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Abstract

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) results from the deterioration of pancreatic ? cells by cellular stressors associated with insulin resistance that can occur during pregnancy, aging and obesity. Through relatively uncharacterized mechanisms, metabolic stress causes ? cells to lose their functional identity by the inactivation of transcription factors important for maintaining the expression of insulin and other factors critica for ? cell function. This proposal examines the potential of the basic helix loop helix (bHLH) transcription factor (TF) NeuroD as an ideal therapeutic target for T2D. NeuroD is critical for the functional maturation, growth and survival of ? cells during development and for maintaining their function in the adult. NeuroD can directly activate the expression of insulin and other factors critical for ? cell function. The 1st aim of this project is to determine how NeuroD regulates ? cell growth and maturation during development. Factors identified in this aim could be useful for differentiating stem cells into functionally mature ? cells and expanding them in culture. The second aim, investigates the mechanism by which NeuroD maintains the expression of insulin and other factors important for ? cell function in the adult. I will examine whether NeuroD is required to maintain the histone acetyl-transferase p300 at the promoters of its targets in order to maintain activating acetylation marks on nearby histones. To investigate why insulin and other NeuroD targets are transcriptionally silenced during the pathogenesis of T2D, I will examine the promoter occupancy of p300, the interaction between NeuroD and p300 and the acetylation status of chromatin near their promoters in the islets of obese T2D mice. I also propose to examine if NeuroD's function is altered by post-translational modifications that occur during the pathogenesis of T2D. To examine the therapeutic potential of NeuroD, I propose to ectopically induce the expression of NeuroD in the ? cells of obese T2D mice, to try to protect and restore their functional ? cells by preserving and reactivating the expression of insulin and other NeuroD targets critical for ? cell function. These experiments would provide mechanistic insight into the pathogenesis of T2D and provide evidence for a novel therapeutic strategy.