E-C coupling efficiency in hibernation and heart failure

描述（由申请人提供）：心脏兴奋-收缩（E-C）偶联的效率在心力衰竭中经历了一个缺陷性的下调，而在冬眠哺乳动物中是上调的。本研究的长期目标是发现冬眠动物E-C偶联调控的细胞和分子机制，并寻求将其应用于抢救衰竭心脏。具体目的、假设和研究设计是：1)验证Ca2+内流倾向于激活肌浆网冬眠时比清醒冬眠者更多的Ca2+释放，从而提高E-C耦合效率的假设。这将通过结合电生理记录和共聚焦Ca2+成像来实现。2)验证在单个E-C偶联单元中，Ca2+释放通道在冬眠期间对单通道Ca2+触发更敏感，而在心力衰竭期间E-C偶联受损时则更敏感的假设。在失败和休眠模型中，分子间耦合保真度、延迟和Ca2+火花的信号质量将使用我们最近开发的松斑共聚焦成像进行分析。3)验证Ca2+单一性质的不同变化是E-C耦合效率在冬眠和心力衰竭中相反变化的基础。通过分析该PI最近发现的Ca2+火花的量子特性，将评估失败和冬眠模型中单通道Ca2+释放和释放通道微招募的强度和动力学。上述研究将揭示E-C偶联在冬眠和心力衰竭中发生的相反修饰的分子细节。这将为进一步研究冬眠动物抢救衰竭心脏的策略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.