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

项目总结： 生物钟的遗传和生活方式紊乱会引发心血管疾病。建议数 这项研究将研究衰老、肥胖和昼夜节律紊乱与心脏新陈代谢障碍之间的联系， 以及限时喂食(TRF)如何缓解这些缺陷。心脏代谢异常的主要危险因素 疾病是年龄、倒班工作、高能量饮食和反常的饮食/睡眠模式。其中的每一个因素 打乱了昼夜节律，在模型生物中已经表明，昼夜节律的遗传扰动 时钟增加了心脏病的发病率和严重程度。例如，一种反常的饮食模式 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，可能是通过打乱生物钟。此外，生物钟基因的突变也容易导致心脏 疾病和光诱导的昼夜节律紊乱会进一步恶化心脏异常。反之，扶轮基金会 不减少卡路里摄入量的范例已被证明可以预防各种新陈代谢紊乱和衰弱 与年龄相关的心脏功能障碍。然而，昼夜节律紊乱与心脏代谢的致病联系 还没有在分子或基因水平上评估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理解 心脏代谢性疾病的病因和减轻。 为了解决这一令人震惊的公共卫生问题的机械基础，我们开发了新的 果蝇(果蝇)模型减轻年龄、肥胖和昼夜节律紊乱引起的心脏 通过施加TRF的进食/禁食节律而导致的疾病。果蝇将成为一个很好的模型系统 昼夜节律、能量代谢和心肌生理学的基本发现。建议的目标1 研究旨在确定TRF在延缓年龄、肥胖挑战、 以及昼夜节律中断导致果蝇心脏生理恶化。目标2：S的目标是监督 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将采用昼夜节律的遗传验证 与其他已识别的基因/途径一起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令人震惊的公众的分子基础 年龄和肥胖引起的心功能障碍与昼夜节律失调相关的健康问题。 成功完成这项建议将极大地加快我们对每日 心肌生理学的节律。扶轮基金会模式可通过以下方式证明适用于人类健康 应用以社区为基础的方法来改善肥胖引起的共病，从而 改善心血管和代谢健康。

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.