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

• 批准号: 10622428
• 负责人: Mariana Gross Figueiro
• 金额: $ 42.66万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10622428
• 关键词: ARNTL gene; Address; Agonist; Area; Arterial Fatty Streak; Atherosclerosis; Beta Cell; Cardiometabolic Disease; Cause of Death; Cell physiology; Cells; Cellular Stress; Cellular Stress Response; Cellular biology; Chronic; Circadian Dysregulation; Circadian desynchrony; Coronary; Coupled; Data; Diabetes Mellitus; Disease; Enhancers; Environment; Exposure to; Foam Cells; General Population; Genes; Genetic; Genetic Models; Glucose; Glucose Intolerance; Heart Diseases; Hepatocyte; Human; Hypothalamic structure; Immune; Indoor environment; Inflammation Mediators; Inflammatory; Insulin; Insulin Resistance; Intervention; Intervention Studies; Lead; Lesion; Light; Lighting; Link; Liver; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Regulation; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral; Pharmacology; Phenotype; Prediabetes syndrome; Risk; Risk Factors; Role; Schedule; Testing; Therapeutic; Tissues; Transcriptional Regulation; United States; Vision; Work; biological adaptation to stress; blind; blood glucose regulation; cardiometabolism; cell type; circadian; circadian biology; circadian pacemaker; endoplasmic reticulum stress; environmental change; environmental intervention; epidemiologic data; experience; gain of function; glucose metabolism; high risk population; insight; insulin signaling; light intensity; lipid metabolism; macrophage; molecular clock; mouse genetics; mouse model; nobiletin; prevent; protective effect; shift work; targeted treatment; transcriptome sequencing; translational potential

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，如轮班工人，易患胰岛素抵抗和2型糖尿病 (T2D)并增加冠状动脉和颈动脉粥样硬化性血管疾病（AVD）的发病率。AVD是导致 糖尿病使AVD的风险增加4倍。然而，迄今为止， 已被证实的干预措施可以预防或减轻昼夜节律紊乱的这些有害影响。因此， 必须确定糖尿病和动脉粥样硬化昼夜节律紊乱的分子基础， 测试有针对性的环境和药物昼夜节律保护干预措施。我们已经表明 在小鼠中，通过删除非冗余核心时钟基因Bmal 1， 导致β细胞的氧化应激和糖尿病。我们的初步数据表明，在小鼠慢性旋转， 轮班工作时间表引起的昼夜节律紊乱与葡萄糖耐受不良和糖尿病有关， 加速动脉粥样硬化和易损斑块表型。来自这些小鼠肝脏的RNA-seq分析 证实了参与氧化和ER应激的基因的富集。最重要的假设是 提出：（1）环境、下丘脑中枢时钟和细胞内源性时钟失去同步 外周生物钟导致胰岛素敏感组织和动脉中细胞应激反应失调 巨噬细胞，导致代谢综合征，T2 D和AVD和（2）使或增强 分子钟功能将减轻昼夜节律紊乱诱导的糖尿病和AVD。我们将使用诱导型， 细胞类型特异性遗传Bmal 1缺失、拯救和功能获得小鼠模型，以机械测试 氧化和内质网（ER）应激途径的不同中枢和外周时钟调节 T2 D和AVD的发病机制。这些再加上时钟调制环境和 对缓解T2 D和AVD风险具有潜在转化意义的药理学干预性研究。 本提案的具体目标是：目标1-测试调制明暗模式（昼夜节律盲，但 视觉允许的）将预防或减轻昼夜节律紊乱诱导的T2 D和AVD。目标2- 药理学时钟调节以减轻昼夜节律紊乱诱导的T2 D和AVD。目标3-遗传 在中枢和外周时钟中缺失和拯救Bmal 1，以确定细胞特异性的 昼夜节律发病机制中细胞应激反应转录调节的内在时钟 糖尿病诱导的T2 D和AVD。本多PI提案来自由三名PI组成的跨学科团队， 在昼夜节律生物学、昼夜节律破坏的遗传模型、糖尿病和新陈代谢方面的互补专业知识 (Dr. Yechoor），照明干预，与工作相关的昼夜节律中断（Figueland博士），AVD，其分子 机制和泡沫细胞生物学（保罗博士）。这些目标的成功实现将为我们提供 深入了解昼夜节律紊乱的心脏代谢后果，并可能导致可翻译的 药理学和/或环境干预。