Calcineurin's role in circadian regulation of cardiac function and remodeling

描述（由申请人提供）： 昼夜节律是分子、生物化学和行为参数的自我维持的24小时周期，帮助生物体为预期的生理需求变化做好准备。许多重要的心血管因素，包括新陈代谢，心率，血压和激素释放，在24小时内振荡。在人类中，不良心脏事件（如心肌梗死、室性心动过速和缺血性心脏病死亡）的发生率根据一天中的时间而变化，昼夜节律的强制性变化与心力衰竭风险增加相关。心血管疾病是美国的主要死亡原因，其发病率在世界范围内达到流行病的比例。尽管有压倒性的证据表明昼夜节律在心血管健康中的重要性，但关于控制心脏功能和重塑的细胞内信号通路的昼夜节律调节知之甚少。我们最近发现了正常健康心脏中钙激活蛋白磷酸酶钙调神经磷酸酶活性的昼夜节律振荡的证据。这一发现是值得注意的，因为钙调神经磷酸酶的激活主要被认为是一个病理过程驱动心脏肥大和衰竭。我们假设钙调神经磷酸酶活性的每日振荡与其他细胞过程形成相互依赖的反馈回路，有助于协调心脏功能的变化和重塑，以适应生理需求的变化。此外，我们推测，钙调神经磷酸酶活性的正常时间关系的中断增加心脏应激，并有助于心脏功能的恶化。这项资助的目的是确定钙调神经磷酸酶活性昼夜变化的原因，并确定钙调神经磷酸酶依赖性振荡在心脏健康和疾病中的作用。具体目标1：确定钙调神经磷酸酶活性昼夜节律的潜在因素。我们将测试是否外在因素，如体力活动，或内在因素，如心肌细胞自主钙振荡的主要原因背后的昼夜激活钙调磷酸酶。具体目标2：确定钙调神经磷酸酶依赖性活动的昼夜变化影响心脏功能的机制.我们将研究调节蛋白磷酸化的变化和钙调神经磷酸酶/NFAT途径的直接转录靶点。具体目标3：测试正常昼夜节律的破坏是否促进心脏的病理性重塑。改变的光照方案和具有改变的钙调磷酸酶活性的转基因品系将用于破坏正常的昼夜节律。将评估动物承受压力超负荷时心脏功能和存活率的变化以及目标1和2中探索的分子机制的变化。(End摘要）

DESCRIPTION (provided by applicant): Circadian rhythms are self-sustaining, 24-hour cycles in molecular, biochemical, and behavioral parameters that help an organism prepare for anticipated changes in physiological demand. Many important cardiovascular factors, including metabolism, heart rate, blood pressure, and hormone release, oscillate over a 24-hour period. In humans, the incidence of adverse cardiac events, such as myocardial infarction, ventricular tachycardia, and death from ischemic heart disease, vary according to the time of day, and forced changes in circadian rhythm are associated with increased risk for heart failure. Cardiovascular disease is the major cause of death in the United States and its incidence is reaching epidemic proportions worldwide. Despite overwhelming evidence of the importance of circadian rhythms in cardiovascular health, little is known regarding the circadian regulation of intracellular signaling pathways controlling cardiac function and remodeling. We have recently found evidence of large circadian oscillations in the activity of the calcium-activated protein phosphatase calcineurin in normal, healthy hearts. This finding is remarkable because activation of calcineurin has primarily been thought of as a pathological process driving cardiac hypertrophy and failure. We hypothesize that daily oscillations in calcineurin activity form interdependent feedback loops with other cellular processes helping to coordinate changes in cardiac function and remodeling in anticipation of changes in physiological demand. Furthermore, we postulate that disruption of the normal temporal relationship of calcineurin activity increases cardiac stress and contributes to deterioration of cardiac function. The goal of this grant is to identify the cause of circadian changes in calcineurin activity and to determine the role of calcineurin-dependent oscillations in cardiac health and disease. Specific Aim 1: To identify factors underlying the circadian rhythm in calcineurin activity. We will test whether extrinsic factors, such as physical activity, or intrinsic factors, such as cardiomyocyte- autonomous calcium oscillations are the primary cause underlying circadian activation of calcineurin. Specific Aim 2: To determine mechanisms through which circadian changes in calcineurin- dependent activities impact cardiac function. We will examine both changes in phosphorylation of regulatory proteins and direct transcriptional targets of the calcineurin/NFAT pathway. Specific Aim 3: To test whether disruption of normal circadian rhythms promotes pathological remodeling of the heart. Altered light regimens and transgenic lines with altered calcineurin activity will be used to disrupt normal circadian rhythmicity. Changes in cardiac function and survival when the animals are subjected to pressure overload will be assed as well as changes in the molecular mechanisms explored in Aims 1 and 2. (End of Abstract)