Mechanoelectrical Transduction in the Myocardium

描述（由申请人提供） 这项研究将与弗拉基米尔Markhasin教授合作，主要在俄罗斯科学院乌拉尔分校免疫学和生理学研究所进行，作为NIH资助5 RO 1HL 5488704的延伸。 实验和临床数据表明，心律失常可能是由于机械输入通过机械-电反馈（MEF）耦合到电输出引起的。在细胞水平上，MEF的关键机制之一是激活心脏组织中的机械敏感通道（MSC）。父母补助金特别关注MSC的一般特性，以及它们在影响动作电位（AP）中的作用。另一种机制提供机械效应的Ca 2+处理被证明是机械依赖性的协同调节肌钙蛋白C对Ca 2+的亲和力。我们推测机械诱导的Ca 2+动力学变化可能通过Na+/Ca 2+交换改变电流的时程，从而影响AP持续时间。据我们所知，MSC与Na+/Ca 2+电流在正常或病理状态下的相互作用，无论是实验上还是理论上都还没有研究。在提议的FIRCA项目中，我们将测试转运抑制剂，特别是阻断MSC的GsMTx-4肽（由PI提供）和Ca 2+处理的调节剂（作为Na+/Ca 2+电流阻断剂）对小梁和乳头肌的一维制备物的收缩性、动作电位构型和细胞内Ca 2+动力学的影响。为了预测实验结果的细胞内机制，我们将开发等电位细胞的数学模型，并阐明MSC的作用及其对心律失常起源的比较贡献。 在整个心脏中已经很好地确立，在收缩期间机械应变的分布在机电功能中起关键作用。这证明我们的下一个目标是开发心肌组织的一维和二维数学模型（虚拟支架），并探讨变形引起的应力/应变场对虚拟组织的机电响应和Ca 2+动力学的影响。俄罗斯团队在研究心肌机械活动方面具有良好的专业知识，无论是在分离的肌条上进行实验还是在理论上通过计算机建模。他们的模型成功地模拟了肌肉力量和长度的时间过程，以及在不同模式的肌肉负荷和动态变形下收缩期间的Ca 2+动力学和电活动。我们将利用俄罗斯的专业知识进行进一步的模型开发，以研究在模拟生理条件下心肌收缩-兴奋耦合的影响。

DESCRIPTION (provided by applicant) This research will be done in collaboration with Prof. Vladimir Markhasin primarily in Russia at Institute of Immunology and Physiology of Ural Brach of Russian Academy of Sciences, as an extension of NIH grant 5RO1HL5488704. Experimental and clinical data evidence that cardiac arrhythmias might result from coupling of mechanical inputs to electrical outputs through mechano-electric feedback (MEF). One of the key mechanisms underlying MEF at the cellular level is activation of mechanosensitive channels (MSCs) in heart tissue. The parent grant concerns specifically the general properties of MSCs, and their role in affecting action potentials (AP). Another mechanism providing mechanical effects on Ca 2+ handling is proved to be the mechano-dependent cooperative modulation of the affinity of troponin C for Ca 2+. We hypothesized that mechanically induced changes in Ca 2+ kinetics may alter the time course of the currents via Na+/Ca 2+ exchange, and thus affect AP duration. As far as we know, the interaction of MSC and Na+/Ca 2+ currents in normal or pathological conditions has not been studied either experimentally or theoretically. Within proposed FIRCA project we are going to test the effects of transport inhibitors, notably GsMTx-4 peptide (supplied by the PI) that block MSCs, and modulators of Ca 2+ handling (as Na+/Ca 2+ currents blockers), on the contractility, action potential configuration and intracellular Ca 2+ dynamics in one dimensional preparations of trabeculae and papillary muscles. To predict intracellular mechanisms of the experimental findings we will develop mathematical models of isopotential cells, and elucidate the role of the MSCs in and their comparative contribution to the origin of cardiac rhythm disturbances. It is well established in the whole heart that the distribution of mechanical strain during a systole plays a key role in the electromechanical function. This justifies our next goal to develop 1D and 2D mathematical models of myocardial tissue (virtual stands), and explore the influence of the deformation-induced stress/strain fields on electromechanical responses of virtual tissue and Ca 2+ kinetics. The Russian team has good expertise in studying mechanical activity of myocardium both experimentally on isolated muscle strips and theoretically by computer modeling. Their models successfully simulate the time course of muscle force and length together with Ca 2+ kinetics and electrical activity during contractions under different modes of muscle loading, and dynamical deformations. We will utilize Russian expertise for further model developing to study effects of contraction - excitation coupling in myocardium under simulated physiological conditions.