Molecular Clock Regulation of b-cell Gene Networks in T1DM

This proposal aims to identify the spectrum of genes controlled by circadian clock components CLOCK and BMAL1 and to delineate their functions in regulating insulin secretion, proliferation, and survival in human pancreatic β-cells. Our previous research led to the exciting discovery that the circadian clock plays an essential role in β-cell development and function in mice and that disruption of the clock leads to hypoinsulinemia and diabetes mellitus. The circadian clock is encoded by a transcription-translation feedback loop involving activators (CLOCK/BMAL1) that induce the expression of repressors (CRY/PER) that inhibit their own expression in an autoregulatory cycle that repeats itself every 24-hours. The identification of molecular clock genes led to rapid advances demonstrating that these genes are expressed both in brain and peripheral tissues, including pancreatic islet cells, where they generate 24-hour oscillations in the expression of ~10% of the transcriptome. Meanwhile, epidemiologic and clinical studies show that disruption of circadian rhythm impacts human β-cell function and microarray transcriptional profiling in humans indicates that Bmal1 is among the most significantly down-regulated transcripts in islets isolated from diabetic donors. We therefore seek to uncover direct targets of CLOCK/BMAL1 in human islet β-cells (Aim #1) and determine how clock disruption impacts epigenetic modification and expression of key secretory, survival, and proliferative gene networks (Aim #2).