Clock modulation in circadian desynchrony induced diabetes and atherovascular disease - mechanisms and interventions

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Circadian disruption, such as that seen in shift workers, predisposes to insulin resistance and type 2 diabetes (T2D), and increases the rates of coronary and carotid atherovascular disease (AVD). AVD is the leading cause of death in the United States and diabetes increases the risk of AVD by 4-fold. However, to date there are no proven interventions that prevent or mitigate these deleterious effects of circadian disruption. It is, therefore, imperative to define the molecular underpinnings of circadian disruption on diabetes and atherosclerosis and to test targeted environmental and pharmacological circadian protective interventions. We have shown previously that in mice genetic disruption of the circadian clock, by deletion of Bmal1, a non-redundant core clock gene leads to oxidative stress in β-cells and diabetes. Our preliminary data demonstrates that in mice chronic rotating shift work schedule-induced circadian disruption is associated with glucose intolerance and diabetes, and with accelerated atherosclerosis and vulnerable plaque phenotypes. RNA-seq analysis from livers of these mice demonstrated enrichment of genes involved in oxidative and ER stress. The overarching hypothesis for this proposal is (1) loss of synchronization between environment, hypothalamic central clock and cell-intrinsic peripheral clocks leads to dysregulation of cellular stress responses in insulin-sensitive tissues and arterial macrophages, resulting in metabolic syndrome, T2D and AVD and (2) resynchronizing or enhancing the molecular clock function will mitigate circadian desynchrony-induced diabetes and AVD. We will use inducible, cell-type specific genetic Bmal1 deletion, rescue and gain-of-function mouse models to mechanistically test the differential central and peripheral clock regulation of oxidative and endoplasmic-reticulum (ER) stress pathways in the pathogenesis of T2D and AVD. These are coupled with clock-modulating environmental and pharmacological interventional studies of potential translational significance to mitigate risk of T2D and AVD. The SPECIFIC AIMS for this proposal are: Aim 1- To test if modulating light-dark patterns (circadian-blind but vision-permissive) will prevent or mitigate circadian desynchrony-induced T2D and AVD. Aim 2- Pharmacological clock modulation to mitigate circadian desynchrony-induced T2D and AVD. Aim 3- Genetic deletion and rescue of Bmal1 in central and peripheral clocks to determine the cell-specific requirement of intrinsic clocks in transcriptional regulation of cellular stress responses in the pathogenesis of circadian desynchrony-induced T2D and AVD. This Multi-PI proposal is from an interdisciplinary team of three PIs with complementary expertise in circadian biology, genetic models of circadian disruption diabetes and metabolism (Dr. Yechoor), lighting interventions, work-related circadian disruption (Dr. Figueiro), AVD, its molecular mechanisms and foam cell biology (Dr. Paul). The successful completion of these aims will provide mechanistic insight into the cardiometabolic consequences of circadian desynchrony and possibly lead to translatable pharmacological and/or environmental interventions.