Role of the Molecular Circadian Clock within the Heart

描述（由申请人提供）：大鼠心脏拥有一个功能齐全的生物钟。生物钟本质上是由调节细胞适应环境变化的分子机制维持的。因此，这些生物钟通过提供一种预测变化的机制，赋予了一种选择优势。然而，目前尚不清楚，心脏内的生物钟预期的环境刺激是什么。心血管参数的日变化（如血压、心率和心输出量）以及心血管疾病的发病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，该提议的主要目的是验证这样一种假设，即心脏内的生物钟同步心脏对环境刺激的昼夜变化的反应，而这种机制的损害导致心脏无法对这些刺激的发作做出适当的反应（即适应不良）。第一个具体目标是研究生物钟在心脏中的潜在生理作用。首先，我们将充分表征心脏内的生物钟，利用分离的成年大鼠心肌细胞。接下来，我们将讨论生物钟允许心脏预测的环境刺激的本质。我们打算研究大鼠心脏是否预测底物可用性、工作量和/或能量供需比的日变化。第二个具体目标将解决啮齿动物心脏生物钟受损的后果，这是由于压力过载引起的肥大，光/暗周期的操纵，以及产生具有心脏特异性废除生物钟的转基因小鼠模型。这些研究将有助于识别心脏中生物钟调节的基因，阐明心脏中生物钟调节的过程，以及确定生物钟损伤对心功能的影响。人类衰竭的心脏是否会改变生物钟也将被研究。我们的长期目标是建立心脏生物钟的分子机制和生理作用，并确定这一机制受损的病理生理后果。

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.