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: 10656450
• 负责人: Girish C. Melkani
• 金额: $ 37.13万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656450
• 关键词: Acceleration; Address; Adult; Affect; Age; Aging; Attenuated; Behavioral; Biological Clocks; Biological Models; Caloric Restriction; Calories; Cardiac; Cardiac health; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Circadian Dysregulation; Circadian Rhythms; Communities; Consumption; Cytoskeleton; 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; Muscle; Mutation; Myocardial dysfunction; Myocardium; Nutrient; Obesity; Oxidative Stress; Pathogenicity; Pathologic; Pathway interactions; Pattern; Performance; Physiological; Physiology; Proteins; Public Health; Publishing; RNA; Rest; Risk; Risk Factors; Role; Sampling; Series; Severities; 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; dietary control; experimental study; feeding; fly; heart disease risk; heart function; human old age (65+); improved; knock-down; model organism; muscle physiology; novel; obesogenic; pharmacologic; 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.

项目总结:

项目成果

Time-restricted feeding regulates lipid metabolism under metabolic challenges.

限时喂养可调节代谢挑战下的脂质代谢。

• DOI: 10.1002/bies.202300157
• 发表时间: 2023
• 期刊: BioEssays : news and reviews in molecular, cellular and developmental biology
• 作者: Guo,Yiming;Livelo,Christopher;Melkani,GirishC
• 通讯作者: Melkani,GirishC

Mitochondrial epigenetic modifications and nuclear-mitochondrial communication: A new dimension towards understanding and attenuating the pathogenesis in women with PCOS.

• DOI: 10.1007/s11154-023-09789-2
• 发表时间: 2023-04
• 期刊: REVIEWS IN ENDOCRINE & METABOLIC DISORDERS
• 影响因子: 8.2
• 作者: Shukla, Pallavi;Melkani, Girish C.
• 通讯作者: Melkani, Girish C.

Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila.

• DOI: 10.3389/fnagi.2023.1223911
• 发表时间: 2023
• 期刊: Frontiers in aging neuroscience
• 影响因子: 4.8

A Skeletal Muscle-Centric View on Time-Restricted Feeding and Obesity under Various Metabolic Challenges in Humans and Animals.

• DOI: 10.3390/ijms24010422
• 发表时间: 2022-12-27
• 期刊: International journal of molecular sciences
• 影响因子: 5.6