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:
- 金额:$ 65.89万
- 依托单位:
- 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
- 来源:
- 关键词:ARNTL geneAccelerationAddressAgonistAreaArterial Fatty StreakAtherosclerosisBeta CellCardiometabolic DiseaseCause of DeathCell physiologyCellsCellular StressCellular biologyChronicCircadian DysregulationCircadian desynchronyCoronaryCoupledDarknessDataDiabetes MellitusDiseaseEnhancersEnvironmentExposure toFoam CellsGeneral PopulationGenesGeneticGenetic ModelsGlucoseGlucose IntoleranceHeart DiseasesHepatocyteHumanHypothalamic structureImmuneIndoor environmentInflammation MediatorsInflammatoryInsulinInsulin ResistanceInterventionIntervention StudiesLeadLesionLightLinkLiverMacrophageMetabolic DiseasesMetabolic syndromeMetabolismMolecularMusNon-Insulin-Dependent Diabetes MellitusOxidative RegulationOxidative StressPathogenesisPathway interactionsPatientsPatternPeripheralPhenotypePhototherapyPrediabetes syndromeRiskRisk FactorsRoleRotationScheduleTestingTherapeuticTissuesTranscriptional RegulationUnited StatesVisionWorkbiological adaptation to stressblindblood glucose regulationcardiometabolismcell typecircadiancircadian biologycircadian pacemakercomparison controlendoplasmic reticulum stressenvironmental changeenvironmental interventionepidemiologic dataexperiencegain of functionglucose metabolismhigh risk populationinsightinsulin signalinglight intensitylipid metabolismmolecular clockmouse geneticsmouse modelnobiletinpermissivenesspharmacologicpreventprotective effectresponserisk mitigationshift worktargeted treatmenttranscriptome sequencingtranslational potential
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,如倒班工人,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疾病(AVD)的发生率。AVD是主要原因
在美国,死亡的风险和糖尿病使AVD的风险增加4倍。然而,到目前为止,还没有
经过验证的干预措施,可以防止或减轻这些昼夜节律紊乱的有害影响。因此,它是,
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,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,通过缺失非冗余的核心时钟基因BMal1,导致生物钟的遗传中断
导致β细胞的氧化应激和糖尿病。我们的初步数据表明,在慢性旋转的小鼠中
轮班工作引起的昼夜节律紊乱与糖耐量异常和糖尿病有关,并与
动脉粥样硬化加速和易损斑块表型。这些小鼠肝脏的RNA-seq分析
证实了参与氧化和内质网应激的基因丰富。关于这一点的首要假设
提出的观点是(1)环境、下丘脑中央时钟和细胞内部之间失去同步性
外周时钟导致胰岛素敏感组织和动脉中细胞应激反应的失调
巨噬细胞,导致代谢综合征、T2D和AVD以及(2)重新同步或增强
分子时钟功能将缓解昼夜节律不同步导致的糖尿病和AVD。我们将使用诱导式,
细胞型特异性遗传BMal1缺失、挽救和功能获得小鼠模型的机械测试
氧化应激和内质网应激途径的中枢和外周时钟调控差异
在T2D和AVD的发病机制中起重要作用。这些都与时钟调制环境和
降低T2D和AVD风险的潜在翻译意义的药理学干预研究。
这项提议的具体目标是:目标1-测试是否调制明暗模式(昼夜失明,但
视力允许)将防止或减轻昼夜节律去同步化引起的T2D和AVD。目标2-
药理学时钟调制以减轻昼夜节律不同步导致的T2D和AVD。AIM 3--基因
在中枢和外周时钟中删除和恢复BMal1以确定细胞特异性要求
昼夜节律发病机制中细胞应激反应转录调控的内在时钟
去同步化诱发的T2D和AVD。这份多绩效指标建议书来自一个由三名绩效指标组成的跨学科团队,
在昼夜节律生物学、昼夜节律紊乱糖尿病的遗传模型和代谢方面的互补专业知识
(耶科尔博士),照明干预,与工作相关的昼夜节律紊乱(菲格雷罗博士),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提供机械性的
对昼夜节律不同步的心脏代谢后果的洞察,并可能导致可翻译
药理和/或环境干预。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mariana Gross Figueiro其他文献
Mariana Gross Figueiro的其他文献
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{{ truncateString('Mariana Gross Figueiro', 18)}}的其他基金
Filtered eyewear to prevent light-induced melatonin suppression while maintaining visual performance and alertness in night-shift working nurses
过滤眼镜可防止光引起的褪黑激素抑制,同时保持夜班护士的视觉表现和警觉性
- 批准号:
10639722 - 财政年份:2023
- 资助金额:
$ 65.89万 - 项目类别:
Supporting health equity with bias-free pulse oximetry
通过无偏差脉搏血氧测定法支持健康公平
- 批准号:
10701873 - 财政年份:2022
- 资助金额:
$ 65.89万 - 项目类别:
Studying 24-hour rhythms of light exposure, alignment with rest-activity cycle, and cardiometabolic health in a nationally representative sample
在全国代表性样本中研究 24 小时光照节律、与休息活动周期的一致性以及心脏代谢健康
- 批准号:
10516569 - 财政年份:2022
- 资助金额:
$ 65.89万 - 项目类别:
Studying 24-hour rhythms of light exposure, alignment with rest-activity cycle, and cardiometabolic health in a nationally representative sample
在全国代表性样本中研究 24 小时光照节律、与休息活动周期的一致性以及心脏代谢健康
- 批准号:
10668466 - 财政年份:2022
- 资助金额:
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Systematic Light Exposure Effects on Circadian Rhythms Entrainment, Inflammation, Neutropenic Fever and Symptom Burden among Multiple Myeloma Patients undergoing Autologous Stem Cell Transplantation
系统性光照对接受自体干细胞移植的多发性骨髓瘤患者的昼夜节律拖累、炎症、中性粒细胞减少性发热和症状负担的影响
- 批准号:
10392164 - 财政年份:2022
- 资助金额:
$ 65.89万 - 项目类别:
Systematic Light Exposure Effects on Circadian Rhythms Entrainment, Inflammation, Neutropenic Fever and Symptom Burden among Multiple Myeloma Patients undergoing Autologous Stem Cell Transplantation
系统性光照对接受自体干细胞移植的多发性骨髓瘤患者的昼夜节律拖累、炎症、中性粒细胞减少性发热和症状负担的影响
- 批准号:
10670054 - 财政年份:2022
- 资助金额:
$ 65.89万 - 项目类别:
Supporting health equity with bias-free pulse oximetry
通过无偏差脉搏血氧测定法支持健康公平
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10571419 - 财政年份:2022
- 资助金额:
$ 65.89万 - 项目类别:
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:
10454373 - 财政年份:2021
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Methodology Issues in a Tailored Light Treatment for Persons with Dementia
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10320581 - 财政年份:2021
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为痴呆症患者量身定制光疗的方法学问题
- 批准号:
10570263 - 财政年份:2021
- 资助金额:
$ 65.89万 - 项目类别:
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