Role of the Molecular Circadian Clock within the Heart

描述(申请人提供)：大鼠心脏拥有一个功能齐全的生物钟。生物钟本质上是由分子机制维持的，这些分子机制使细胞适应环境的变化。因此，这些生物钟提供了一种预测变化的机制，从而赋予了一种选择性优势。然而，目前尚不清楚心脏内的生物钟预计会产生什么样的环境刺激。心血管参数(如血压、心率和心输出量)的昼夜变化以及心血管疾病的发生以前被归因于神经体液因素(如交感神经活动)。相比之下，刺激-反应耦合的第二个组成部分，即系统对刺激的敏感性，在很大程度上被忽视了。因此，这一建议的主要目标是检验一种假设，即心脏内的生物钟使心脏对其环境刺激的昼夜变化的反应同步，并且这一机制的损害导致心脏无法对这种刺激的开始做出适当的反应(即适应不良)。第一个具体目标是研究生物钟在心脏内的潜在生理作用(S)。首先，我们将利用分离的成年大鼠心肌细胞，充分描述心脏内的生物钟。接下来，我们将讨论生物钟允许心脏预测的环境刺激的性质。我们打算调查大鼠心脏是否预测到底物可利用性、工作负荷和/或能量供需比的日变化。第二个具体目标将解决由于压力超负荷引起的啮齿动物心脏生物钟受损的后果，操纵光明/黑暗周期，以及产生心脏特有的取消生物钟的转基因小鼠模型。这样的研究将有助于识别心脏中的生物钟调节基因，阐明心脏中的生物钟调节过程，以及确定生物钟损伤对心脏功能的影响。还将调查衰竭的人类心脏的生物钟是否发生了变化。我们的长期目标是建立心脏内生物钟的分子机制和生理作用(S)，并确定这一机制受损的病理生理学后果。

DESCRIPTION (provided by applicant): The rat heart possesses a fully functional circadian clock. Circadian clocks are intrinsically maintained by molecular mechanisms that condition the cell to changes in its environment. These circadian clocks therefore confer a selective advantage by providing a mechanism for anticipation of change. It is not known, however, which environmental stimuli the circadian clock within the heart anticipates. Diurnal variations in cardiovascular parameters (such as blood pressure, heart rate, and cardiac output) as well as the onset of cardiovascular disease have previously been attributed to neurohumoral factors (e.g. sympathetic activity). In contrast, the second component of stimulus-response coupling, namely the sensitivity of the system to the stimulus, has been largely ignored. The broad objective of this proposal is therefore to test the hypothesis that the circadian clock within the heart synchronizes responsiveness of the heart to diurnal variations in its environmental stimuli, and that impairment of this mechanism results in an inability of the heart to respond appropriately to the onset of such stimuli (i.e. maladaptation). The first specific aim will investigate the potential physiological role(s) of the circadian clock within the heart. Initially we will fully characterize the circadian clock within the heart, utilizing isolated adult rat cardiomyocytes. Next, we will address the nature of the environmental stimuli that the circadian clock allows the heart to anticipate. We intend to investigate whether the rat heart anticipates diurnal variations in substrate availability, workload and/or the energy supply/demand ratio. The second specific aim will address the consequences of impairment of the circadian clock within the heart of rodents due to pressure overload-induced hypertrophy, manipulation of the light/dark cycle, and the generation of a transgenic mouse model with a heart-specific abolition of the circadian clock. Such studies will allow identification of circadian clock-regulated genes in the heart, elucidation of circadian clock-regulated processes in the heart, as well as determination of the consequences of circadian clock impairment on cardiac function. Whether the circadian clock is altered in the failing human heart will also be investigated. Our long-term goals are to establish the molecular mechanisms and physiological role(s) of the circadian clock within the heart, and to determine the pathophysiological consequences of impairment of this mechanism.