Role of the Molecular Circadian Clock within the Heart

描述（由申请人提供）：大鼠心脏具有功能齐全的生物钟。生物钟本质上是由分子机制维持的，这些机制使细胞适应环境的变化。因此，这些生物钟通过提供预测变化的机制而赋予选择性优势。然而，目前还不知道心脏内的生物钟预期哪些环境刺激。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作以前被归因于神经体液因素（如交感神经活动）。相反，刺激-反应耦合的第二个组成部分，即系统对刺激的敏感性，在很大程度上被忽略了。因此，本提案的广泛目标是检验以下假设：心脏内的昼夜节律钟抑制心脏对其环境刺激的昼夜变化的反应性，并且该机制的损伤导致心脏不能适当地对此类刺激的开始作出反应（即，适应不良）。第一个具体目标是研究心脏内生物钟的潜在生理作用。首先，我们将充分表征心脏内的昼夜节律钟，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期的环境刺激的性质。我们打算调查是否大鼠心脏预期昼夜变化的底物的可用性，工作量和/或能源供应/需求比。第二个具体目标将解决由于压力过载诱导的肥大、操纵光/暗周期以及产生具有心脏特异性生物钟消除的转基因小鼠模型而导致啮齿动物心脏内生物钟受损的后果。这些研究将允许识别心脏中的昼夜节律钟调节基因，阐明心脏中的昼夜节律钟调节过程，以及确定昼夜节律钟损伤对心脏功能的后果。我们还将研究衰竭的人类心脏的生物钟是否会改变。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，并确定该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.