Role of the Molecular Circadian Clock within the Heart

描述(申请人提供)：人类在多种心血管(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。到目前为止，生理性心血管参数的昼夜节律被归因于相同的神经体液刺激(例如交感神经活动)，这些刺激被认为是导致致命性心血管事件(例如心肌梗死、心律失常和心源性猝死)的原因。我们的研究揭示了心肌细胞内一种新的分子机制，它在一天的过程中直接调节心肌基因的表达、代谢和功能。这种机制就是心肌细胞内的生物钟。生物钟是基于转录的机制，赋予预期的选择性优势，使心肌细胞/心脏在它们开始时对环境刺激做出快速和适当的反应。这项建议的主要目的是检验一种假设，即心肌细胞内的生物钟同步心脏对环境的反应，并且这一机制的损害会导致心脏无法对其环境做出适当的反应(即适应不良)。心肌代谢改变在肥厚性、糖尿病和缺血性心脏病相关的收缩功能障碍的发病机制中起着核心作用，这些疾病是指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；以及2)确定心肌细胞内的生物钟受损的病理生理后果。在这些研究中，我们将利用我们独特的小鼠模型，在该模型中，生物钟在心肌细胞中受到特定的损害。对于特定的目标1，我们将利用分离的工作小鼠心脏来识别心肌细胞通道内的生物钟脂肪酸和葡萄糖进入氧化和非氧化途径的机制。对于特定的目标2，我们将研究心肌细胞内生物钟的损伤是否会增加缺血/再灌注、糖尿病、压力超负荷、衰老和/或模拟的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心血管疾病发展之间的因果联系。

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.