Appropriate mass and regulated function of pancreatic islet -cells are essential features of human health. Glucose metabolism, membrane depolarization and Ca2+ transients induce transcriptional changes that stimulate -cell development and functional maturation in post-natal islets. However, the molecular mechanisms linking -cell physiological activity to post-natal -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 -cells. What are the native mechanisms that govern Cn/NFATc signaling in islet -cells? Our studies indicate that protein kinases, including Dyrk1a, regulate -cell NFATc signaling. We postulate that these mechanisms are modulated in diseases like type 2 diabetes where -cells are dysfunctional, and are required for development of functional replacement -cells in type 1 diabetes. To address these fundamental questions in both mouse and human -cells, we propose Specific Aims to: 1. Elucidate in vivo Dyrk1a-dependent mechanisms controlling NFATc signaling in mouse and human islet -cells. 2. Use innovative genomic-scale methods that comprehensively identify open chromatin and NFATc target genes in mouse and human -cells. 3. Identify NFATc1-recruited nuclear coregulators that govern -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 -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 -cells. Thus, our work may have broad impact by suggesting strategies for controlling islet cell function and fate, to ameliorate defective -cell function in type 2 diabetics, and create functional replacement -cells for type 1 diabetics.
Loss of functioning pancreatic -cells, the sole source of the hormone insulin, is a principal basis for all forms of diabetes mellitus in humans. Thus, a detailed understanding of the natural regulators of -cell function would benefit efforts to improve or replace beta cells in this serious and expanding disease. Here we use innovative molecular methods to elucidate how -cells control their specialization into mature, functional cells.