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: 10307949
• 负责人: Girish C. Melkani
• 金额: $ 31.92万
• 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/10307949
• 关键词: Molecular; basis; circadian; rhythms; disruptions

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： 遗传和生活方式对生物钟的干扰会引发心血管疾病。拟议 这项研究将探讨衰老、肥胖和昼夜节律紊乱如何与心脏代谢紊乱联系在一起， 以及时间限制进料（TRF）如何减轻这些缺陷。心血管疾病的主要危险因素 疾病是年龄、轮班工作、高能量饮食和异常的饮食/睡眠模式。这些因素中的每一 扰乱昼夜节律，并且在模式生物中已经表明，昼夜节律的遗传干扰 生物钟增加了心脏病的发病率和严重程度。例如，一个异常的饮食模式， 在控制饮食后，人类患心血管疾病的风险增加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， 疾病和光诱导的昼夜节律紊乱进一步恶化了心脏异常。相反，TRF 在不减少热量摄入的情况下，已经显示出预防各种代谢紊乱和减弱 与年龄相关的心功能障碍然而，昼夜节律钟中断与心脏代谢的致病性联系， 然而，目前尚未在分子或遗传水平上评估TRF干预的潜在益处。 因此，我们的科学前提是，影响昼夜节律的因素提供了新的途径来了解 心脏代谢紊乱的病因学和衰减。 为了解决这一令人震惊的公共卫生问题的机制基础，我们开发了新的 果蝇（果蝇）模型，以减轻年龄，肥胖和昼夜节律紊乱诱导的心脏 通过使用TRF强制进食/禁食节律来治疗疾病。果蝇将作为一个很好的模型系统， 生理节律、能量代谢和心肌生理学的基本发现。拟议目标1 研究的目的是确定TRF在延缓衰老、致肥胖挑战 和昼夜节律紊乱引起的果蝇心脏生理恶化。目标2的目标是监测 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将采用生物钟的遗传验证 时钟与其他已确定的基因/途径介导的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年龄和肥胖引起的心脏功能障碍的健康问题。 成功完成这一提案将大大加快我们对日常影响的理解 对心脏肌肉生理的影响。扶轮基金会范例可能证明适用于人类健康， 应用基于社区的方法改善肥胖引起的合并症， 改善心血管和代谢健康。