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

昼夜节律不同步引起的糖尿病和动脉粥样硬化疾病的时钟调节 - 机制和干预措施

基本信息

批准号：
10614035
负责人：
Mariana Gross Figueiro
金额：
$ 65.89万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-20 至 2026-04-30
项目状态：
未结题

项目摘要

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.

昼夜节律紊乱，例如轮班工人的昼夜节律紊乱，容易导致胰岛素抵抗和 2 型糖尿病 (T2D)，并增加冠状动脉和颈动脉粥样硬化血管疾病 (AVD) 的发病率。在美国，死亡和糖尿病会使 AVD 的风险增加 4 倍，但迄今为止还没有发现这种情况。因此，经过验证的干预措施可以预防或减轻环昼夜扰乱的这些有害影响。必须明确昼夜节律紊乱对糖尿病和动脉粥样硬化的分子基础，并测试有针对性的环境和药理学昼夜节律保护干预措施，我们之前已经展示过。在小鼠中，通过删除 Bmal1（一种非冗余的核心时钟基因），对生物钟进行基因破坏我们的初步数据表明，在小鼠中，长期旋转会导致β细胞氧化应激和糖尿病。轮班工作引起的昼夜节律紊乱与葡萄糖不耐受和糖尿病有关，并且与加速了这些小鼠肝脏的动脉粥样硬化和易损斑块表型的 RNA-seq 分析。与氧化和内质网应激相关的基因富集是这一点的总体假设。建议是（1）环境、下丘脑中央时钟和细胞固有时钟之间失去同步外周时钟导致胰岛素敏感组织和动脉中的细胞应激反应失调巨噬细胞，导致代谢综合征、T2D 和 AVD 以及 (2) 重新同步或增强分子时钟功能将减轻昼夜节律不同步引起的糖尿病和 AVD。细胞类型特异性遗传 Bmal1 缺失、拯救和功能获得小鼠模型，用于机械测试氧化和内质网（ER）应激途径的中枢和外周时钟差异调节 T2D 和 AVD 的发病机制与时钟调节环境和因素有关。对降低 T2D 和 AVD 风险具有潜在转化意义的药理学介入研究。该提案的具体目标是：目标 1 - 测试是否调制明暗模式（昼夜节律盲但视力许可）将预防或减轻昼夜节律不同步引起的 T2D 和 AVD 目标 2-。药理学时钟调节可减轻昼夜节律不同步引起的 T2D 和 AVD 目标 3-遗传。删除和挽救中央和外周时钟中的 Bmal1，以确定细胞特定的要求昼夜节律发病机制中细胞应激反应转录调节的内在时钟该多 PI 提案来自由三名 PI 组成的跨学科团队，其中包括：昼夜节律生物学、昼夜节律紊乱的遗传模型、糖尿病和新陈代谢方面的互补专业知识（Yechoor 博士）、照明干预、与工作相关的昼夜节律紊乱（Figueiro 博士）、AVD、其分子机制和泡沫细胞生物学（保罗博士）。这些目标的成功完成将提供机制。深入了解昼夜节律不同步对心脏代谢的影响，并可能导致可转化的药理学和/或环境干预。