E-C coupling efficiency in hibernation and heart failure

描述(申请人提供)：虽然心脏兴奋-收缩(E-C)偶联的效率在心力衰竭中经历了缺陷的下调，但在冬眠的哺乳动物中是上调的。这项研究的长期目标是发现冬眠者E-C偶联调节的细胞和分子机制，并寻求将其应用于抢救衰竭的心脏。具体目的、假设和研究设计如下：1)验证钙离子内流倾向于激活肌浆网冬眠者比清醒冬眠者更多的钙释放，从而提高E-C偶联效率的假说。这将通过结合电生理记录和共聚焦钙成像来实现。2)验证以下假设：在单个E-C偶联单位中，钙释放通道在冬眠期间对单通道Ca~(2+)触发更敏感，而在心力衰竭期间E-C偶联受损时反应较弱。我们将使用我们最近开发的松散贴片共聚焦成像来分析失败和冬眠模型中钙离子火花的分子间耦合保真度、潜伏期和信号量。3)验证了冬眠和心力衰竭时钙离子单体性质的不同变化是E-C偶联效率相反变化的假设。通过分析本PI最近发现的钙火花的量子特性，将评估在衰竭和冬眠模型中单通道钙释放的强度和动力学以及释放通道的微观募集。上述研究将揭示冬眠和心力衰竭时E-C偶联相反修饰的分子细节。这将为进一步研究冬眠者运用策略抢救心力衰竭提供必要和重要的依据。

DESCRIPTION (provided by applicant): While the efficiency of cardiac excitation-contraction (E-C) coupling in heart failure undergoes a defective down-regulation, that in hibernating mammals is up-regulated. The long-term objective of the proposed research is to find the cellular and molecular mechanism of E-C coupling regulation in hibernators, and seek to apply them in rescuing failing hearts. The specific aims, hypotheses and research designs are: 1) to test the hypothesis that the Ca2+ influx tends to activate more Ca2+ release from sarcoplasmic reticulum hibernating than awake hibernators such that the E-C coupling efficiency can be increased. This will be achieved by combining electrophysiological recording and confocal Ca2+ imaging. 2) to test the hypothesis that, in a single E-C coupling unit, Ca2+ release channels become more responsive to single-channel Ca2+ trigger during hibernation, but less in impaired E-C coupling during heart failure. The intermolecular coupling fidelity and latency and signal mass of Ca2+ sparks in failing and hibernating models will be analyzed using our recently developed loose-patch confocal imaging. 3) to test the hypothesis that different changes in the unitary properties of Ca2+ underlie the opposite alternation of E-C coupling efficiency in hibernation and heart failure. The strength and kinetics of single-channel Ca2+ release and micro-recruitment of release channels in failure and hibernation models will be assessed by analyzing the quantal property of Ca2+ sparks recently found by this PI. The above study will reveal the molecular details underlying the opposite modifications of E-C coupling occurred in hibernation and heart failure. This will provide necessary and important basis for further studies to rescue failing heart with strategies employed by hibernators.