Role of the Molecular Circadian Clock within the Heart

描述（由申请人提供）：人类在多个心血管（CV）参数中表现出明显的昼夜节律，包括心率、心输出量和血压。迄今为止，生理CV参数中的昼夜节律已归因于被认为导致致死性CV事件（例如心肌梗死、心律失常和心源性猝死）的相同神经体液刺激（例如交感神经活动）。我们的研究揭示了心肌细胞内一种新的分子机制，该机制在一天中直接调节心肌基因表达、代谢和功能。这个机制就是肌细胞内生物钟。昼夜节律钟是基于转录的机制，其赋予预期的选择性优势，使心肌细胞/心脏能够在环境刺激开始时快速且适当地响应。该提案的广泛目标是检验以下假设：心肌细胞内的昼夜节律钟抑制心脏对环境的反应，并且该机制的损伤导致心脏无法对其环境做出适当的反应（即适应不良）。改变的心肌代谢在与肥厚性、糖尿病性和缺血性心脏病相关的收缩功能障碍的发病机制中起核心作用，在这些疾病中心肌细胞内的生物钟受损。因此，我们打算解决以下具体目标：1）确定心肌细胞内的生物钟调节心肌代谢的机制; 2）确定心肌细胞内生物钟受损的病理生理学后果。对于这些研究，我们将利用我们独特的小鼠模型，其中昼夜节律钟在心肌细胞内特异性受损。对于特定目标1，我们将利用分离的工作小鼠心脏来确定心肌细胞内的昼夜节律钟将脂肪酸和葡萄糖引入氧化与非氧化途径的机制。对于具体目标2，我们将研究心肌细胞内的昼夜节律钟的损伤是否增强缺血/再灌注、糖尿病、压力超负荷、衰老和/或模拟轮班工作介导的收缩功能障碍。我们的长期目标是建立心肌细胞内生物钟受损与人类CV疾病发展之间的因果关系。

DESCRIPTION (provided by applicant): Humans exhibit marked circadian rhythms in multiple cardiovascular (CV) parameters, including heart rate, cardiac output, and blood pressure. To date, circadian rhythms in physiological CV parameters have been attributed to the same neurohumoral stimuli (e.g. sympathetic activity) believed to be responsible for fatal CV events (e.g. myocardial infarctions, arrhythmias, and sudden cardiac death). Our studies expose a novel molecular mechanism within cardiomyocytes that directly regulates myocardial gene expression, metabolism, and function over the course of the day. This mechanism is the intramyocellular circadian clock. Circadian clocks are transcriptionally-based mechanisms that confer the selective advantage of anticipation, enabling the cardiomyocyte/heart to respond rapidly and appropriately to environmental stimuli upon their onset. The broad objective of this proposal is to test the hypothesis that the circadian clock within the cardiomyocyte synchronizes responsiveness of the heart to the environment, and that impairment of this mechanism results in an inability of the heart to respond appropriately to its environment (i.e. maladaptation). Altered myocardial metabolism plays a central role in the pathogenesis of contractile dysfunction associated with hypertrophic, diabetic, and ischemic heart disease, conditions in which the circadian clock within the cardiomyocyte is impaired. We therefore intend to address the following specific aims: 1) identify the mechanisms by which the circadian clock within the cardiomyocyte modulates myocardial metabolism; and 2) determine the pathophysiological consequences of impairment of the circadian clock within the cardiomyocyte. For these studies, we will utilize our unique mouse model in which the circadian clock is specifically impaired within cardiomyocytes. For Specific Aim 1, we will utilize isolated working mouse hearts to identify the mechanisms by which the circadian clock within the cardiomyocyte channels fatty acids and glucose into oxidative versus non-oxidative pathways. For Specific Aim 2, we will investigate whether impairment of the circadian clock within the cardiomyocyte augments ischemia/reperfusion-, diabetes mellitus-, pressure overload-, aging-, and/or simulated shift work- mediated contractile dysfunction. Our long-term objectives are to establish causal links between impairment of the circadian clock within the cardiomyocyte with development of CV disease in humans.