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: 10017850
• 负责人: Girish C. Melkani
• 金额: $ 8.93万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2020-10-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017850
• 关键词: Address; Adult; Affect; Age; Aging; Animal Model; Attenuated; Behavioral; Biological Clocks; Biological Models; Caloric Restriction; Calories; Cardiac; Cardiac health; Cardiovascular Diseases; Cardiovascular system; Circadian Dysregulation; Circadian Rhythms; Communities; Consumption; Darkness; Defect; Deterioration; Diet; Dietary Intervention; Disease; 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; cardiometabolism; circadian; circadian pacemaker; comorbidity; detection of nutrient; experimental study; feeding; fly; functional improvement; heart disease risk; heart function; 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.

项目概要： 生物钟的遗传和生活方式扰动会引发心血管疾病。拟议的 研究将探讨衰老、肥胖和昼夜节律紊乱与心脏代谢紊乱之间的关系， 以及限时喂养 (TRF) 如何减轻这些缺陷。心脏代谢的主要危险因素 疾病包括年龄、轮班工作、能量密集型饮食和异常的饮食/睡眠模式。这些因素中的每一个 disrupts circadian rhythms, and it has been shown in model organisms that genetic perturbation of the circadian 时钟增加了心脏病的发病率和严重程度。例如，异常的饮食习惯 控制饮食后，人类患心血管疾病的风险增加高达 55% 和生活方式，可能是由于生物钟的破坏。此外，生物钟基因的突变容易导致心脏病 疾病和光引起的昼夜节律紊乱进一步恶化心脏异常。相反，TRF 不减少热量摄入的范例已被证明可以预防各种代谢紊乱并减轻 与年龄相关的心功能障碍。然而，生物钟紊乱与心脏代谢的致病联系 疾病或 TRF 干预的潜在益处尚未在分子或基因水平上进行评估。 因此，我们的科学前提是影响昼夜节律的因素为理解昼夜节律提供了新的途径。 心脏代谢紊乱的病因和减弱。 为了解决这一令人震惊的公共卫生问题的机制基础，我们开发了新颖的 果蝇模型可减轻年龄、肥胖和昼夜节律紊乱引起的心脏病 通过 TRF 强制进食/禁食节律来治疗疾病。果蝇将作为一个优秀的模型系统 昼夜节律、能量代谢和心肌生理学方面的基本发现。拟议的目标 1 研究的目的是确定 TRF 在延缓年龄、肥胖挑战方面有效性的分子基础， 以及昼夜节律紊乱引起的果蝇心脏生理机能恶化。目标 2 的目标是监控 饮食干预对心脏基因表达的昼夜和长期重编程的影响 衰老、肥胖挑战和昼夜节律紊乱。目标 3 将采用昼夜节律基因验证 与其他已确定的基因/途径进行时钟调节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引起公众担忧的分子基础 年龄和肥胖引起的与昼夜节律失调相关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日常影响的理解 节律对心肌生理学的影响。 TRF范式可能通过以下方式证明适用于人类健康： 应用基于社区的方法来改善肥胖引起的合并症，从而 改善心血管和代谢健康。