Molecular basis of circadian rhythms disruptions linked cardiometabolic disorders and their mitigation using dietary intervention

昼夜节律紊乱的分子基础与心脏代谢紊乱及其通过饮食干预的缓解

• 批准号: 10442441
• 负责人: Girish C. Melkani
• 金额: $ 39.07万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442441
• 关键词: Address; Adult; Affect; Age; Aging; Animal Model; Attenuated; Behavioral; Biological Clocks; Biological Models; Caloric Restriction; Calories; Cardiac; Cardiac health; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Circadian Dysregulation; Circadian Rhythms; Communities; Consumption; Darkness; Defect; Deterioration; Diet; Dietary Intervention; Drosophila genus; Drosophila melanogaster; Eating; Effectiveness; Energy Intake; Energy Metabolism; Etiology; Experimental Models; FRAP1 gene; Fasting; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Health; Heart; Heart Abnormalities; Heart Diseases; Hour; Human; Incidence; Industrialization; Intervention; Life; Life Style; Light; Link; Long-Term Effects; Mediating; Metabolic; Metabolic Diseases; Modeling; Molecular; Molecular Genetics; Monitor; Mutation; Myocardial dysfunction; Myocardium; Nutrient; Obesity; Oxidative Stress; Pathogenicity; Pathologic; Pathway interactions; Pattern; Performance; Pharmacology; Physiological; Physiology; Proteins; Public Health; Publishing; RNA; Rest; Risk; Risk Factors; Role; Sampling; Series; Severities; Sleep; Societies; Starvation; Testing; Time; Time-restricted feeding; Treatment Efficacy; Validation; age effect; age related; attenuation; base; cardiometabolic risk; circadian; circadian pacemaker; comorbidity; detection of nutrient; experimental study; feeding; fly; functional improvement; heart disease risk; heart function; human old age (65+); improved; knock-down; muscle physiology; novel; obesogenic; prevent; proteostasis; response; shift work; sleep pattern; time use; tool

Project Summary: Genetic and lifestyle perturbation of the circadian clock trigger cardiovascular diseases. The proposed study will examine how aging, obesity and circadian rhythm disruptions linked with cardiometabolic disorders, and how time-restricted feeding (TRF) mitigates these defects. The leading risk factors for cardiometabolic diseases are age, shift work, energy dense diet and aberrant eating/sleeping patterns. Each of these factors disrupts circadian rhythms, and it has been shown in model organisms that genetic perturbation of the circadian clock increases the incidence and severity of cardiac diseases. For example, an aberrant eating pattern in human, increases the risk of developing cardiovascular diseases by as much as 55%, after controlling for diet and lifestyle, possibly by disruption of circadian clock. Also, mutations of circadian clock genes prone to cardiac diseases and light-induced circadian disruptions further deteriorates cardiac abnormalities. Conversely, TRF paradigm without reducing caloric intake has been shown to prevent various metabolic disorders and attenuates age-linked cardiac dysfunction. However, pathogenic linkage of circadian clock disruptions with cardiometabolic diseases, or the potential benefit of TRF intervention has not been assessed at the molecular or genetic level. Thus, our scientific premise is that factors that affect circadian rhythms offer new avenues to understand the etiology and attenuation of cardiometabolic disorders. To address the mechanistic basis of this alarming public health issue, we have developed novel Drosophila melanogaster (fruit fly) models to mitigate age, obesity and circadian disruption-induced cardiac disorders by imposing feeding/fasting rhythms with TRF. Drosophila will serve as an excellent model system for basic discoveries in circadian rhythms, energy metabolism and cardiac muscle physiology. Aim 1 of the proposed study is to determine the molecular basis of the effectiveness of TRF in delaying age-, obesogenic challenges, and circadian disruption-induced deterioration of cardiac physiology in Drosophila. Aim 2’s goals are to monitor the effect of dietary intervention on the diurnal and long-term reprogramming of cardiac gene expression under aging, obesogenic challenges and circadian rhythms disruption. Aim 3 will employ genetic validation of circadian clock with other identified genes/pathways mediating the effect of eating pattern on cardiac health. Our study will use hypothesis-driven experiments to address the molecular basis of the alarming public health problem of age and obesity-induced cardiac dysfunction associated with circadian dysregulation. Successful completion of this proposal will dramatically accelerate our understanding of the impact of daily rhythms on cardiac muscle physiology. The TRF paradigm may prove applicable to human health through application of community-based approaches to ameliorating obesity-induced comorbidities and thereby improving cardiovascular and metabolic health.

项目摘要： 昼夜节律触发心血管疾病的遗传和生活方式扰动。提议 研究将研究衰老，肥胖和昼夜节律中断与心脏代谢性疾病有关的如何 以及时间限制的进食（TRF）如何减轻这些缺陷。心脏代谢的主要危险因素 疾病是年龄，转移工作，能量密集的饮食和异常的饮食/睡眠方式。这些因素中的每一个 破坏昼夜节律，并在模型生物中显示出昼夜节律的遗传扰动 时钟增加了心脏疾病的事件和严重程度。例如，在 在控制饮食之后 和生活方式，可能会破坏昼夜节律。此外，昼夜节律基因的突变容易受心脏 疾病和光引起的昼夜节律破坏进一步恶化心脏异常。相反，trf 范式没有减少热量摄入量可预防各种代谢障碍和减弱 年龄连接的心脏功能障碍。但是，昼夜节律与心脏代谢的致病连接 尚未在分子或遗传水平上评估疾病或TRF干预的潜在益处。 这就是我们科学的前提是影响昼夜节律的因素为了解新的途径 心脏代谢疾病的病因和衰减。 为了解决这个令人震惊的公共卫生问题的机械基础，我们开发了新颖 果蝇Melanogaster（果蝇）模型，以减轻年龄，肥胖和昼夜节律诱导的心脏 通过用TRF施加喂养/空腹节奏来疾病。果蝇将作为一个出色的模型系统 昼夜节律，能量代谢和心脏肌肉生理学的基本发现。拟议中的目标1 研究是为了确定TRF在延迟年龄，肥胖挑战中的有效性的分子基础， 和昼夜节律诱导的果蝇心脏生理恶化。 AIM 2的目标是监视 饮食干预对心脏基因表达的昼夜和长期重编程的影响 AIM 3将采用昼夜节律的遗传验证 时钟具有其他鉴定的基因/途径，介导饮食模式对心脏健康的影响。 我们的研究将使用假设驱动的实验来解决令人震惊的公众的分子基础 与昼夜节律失调相关的年龄和肥胖引起的心脏功能障碍的健康问题。 该提案的成功完成将极大地加速我们对每日影响的理解 心肌生理的节奏。 TRF范式可能证明适用于人类健康 采用基于社区的方法来改善肥胖引起的合并症，从而应用 改善心血管和代谢健康。