NFAT control of pancreatic islet beta-cell functional maturation

Stanford University, Stanford CA

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Abstract

? DESCRIPTION (provided by applicant): Appropriate mass and regulated function of pancreatic islet ß-cells are essential features of human health. Glucose metabolism, membrane depolarization and Ca2+ transients induce transcriptional changes that stimulate ß-cell development and functional maturation in post-natal islets. However, the molecular mechanisms linking ß-cell physiological activity to post-natal ß-cell development remain incompletely understood. The Ca2+-regulated signaling pathway governed by the phosphatase, calcineurin (Cn), and its target, the Nuclear Factor of Activated T-cells proteins (NFATc), control functional maturation and proliferation in young mouse and human pancreatic islet ß-cells. What are the native mechanisms that govern Cn/NFATc signaling in islet ß-cells? Our studies indicate that protein kinases, including Dyrk1a, regulate ß-cell NFATc signaling. We postulate that these mechanisms are modulated in diseases like type 2 diabetes where ß-cells are dysfunctional, and are required for development of functional replacement ß-cells in type 1 diabetes. To address these fundamental questions in both mouse and human ß-cells, we propose Specific Aims to: 1. Elucidate in vivo Dyrk1a-dependent mechanisms controlling NFATc signaling in mouse and human islet ß-cells. 2. Use innovative genomic-scale methods that comprehensively identify open chromatin and NFATc target genes in mouse and human ß-cells. 3. Identify NFATc1-recruited nuclear coregulators that govern ß-cell maturation. Discovery of endogenous signaling pathways that direct the physiological function of tissues is a principal goal of regenerative and developmental biology. Evolutionarily conserved mechanisms governing post-natal maturation of islet ß-cells should be revealed by studies proposed here. At a fundamental level, our work should establish regulatory paradigms that connect metabolic signaling and transcriptional regulation in pancreatic ß-cells. Thus, our work may have broad impact by suggesting strategies for controlling islet cell function and fate, to ameliorate defective ß-cell function in type 2 diabetics, and create functional replacement ß-cells for type 1 diabetics.