Type 1 diabetes mellitus (T1DM) is characterized by progressive loss of functional pancreatic beta cell mass triggered by beta cell directed autoimmunity, however the latency between onset of autoimmunity and overt diabetes varies among different individuals. The timing of this latency window is thought to involve variation in intrinsic metabolic or stress response mechanisms within beta cells that influence susceptibility to immune attack, although the molecular determinants of this process remain poorly understood. In this context, our research has recently led to the exciting discovery that the circadian clock plays an essential role in beta cell development and function, and that disruption of the clock leads to hypoinsulinemia and diabetes mellitus. At the molecular level, the circadian clock is encoded by bHLH-PAS transcription activators (CLOCK/BMAL1) that induce the transcription of two repressors (CRY/PER) which feed back to inhibit CLOCK/BMAL1 expression in a cycle that repeats itself every 24-hours and in turn produces transcriptional oscillation within the beta cells essential for development, stress response, and survival. In addition, we demonstrate that CLOCK/BMAL1 modulate insulin exocytosis, and therefore may impact antigen release and early islet immunogenicity. Remarkably, we have also found that CLOCK/BMAL1 play a central role in the regulation of cellular NAD+ biosynthesis, a critical component of activation of immune cells. Therefore, in this proposal we seek to test the novel and innovative hypothesis that the circadian clock exerts dual roles at the interface of islets and the immune system and that clock disruption both (1) exacerbates cellular damage and immunogenicity and (2) augments and dysregulates immune cell signaling. Results from our studies will establish new mechanisms-based targets for therapeutic intervention in T1DM.
|Effective start/end date||9/1/13 → 8/31/16|
- JDRF International and The Leona M. and Harry B. Helmsley Charitable Trust (17-2013-511)
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