Mechanoelectrical Transduction in the Myocardium

描述(由申请人提供) 这项研究将与Vladimir Markhasin教授合作完成，主要是在俄罗斯的俄罗斯科学院乌拉尔分支免疫和生理学研究所，作为NIH 5RO1HL5488704拨款的延伸。实验和临床数据表明，心律失常可能是由于机械输入与电输出通过机械电反馈(MEF)耦合而引起的。MEF在细胞水平的关键机制之一是激活心脏组织中的机械敏感通道(MSCs)。父母的资助特别涉及骨髓间充质干细胞的一般性质，以及它们在影响动作电位(AP)中的作用。另一种机械效应机制是肌钙蛋白C对钙离子亲和力的机械协同调节。我们推测，机械诱导的钙动力学改变可能通过钠/钙交换改变电流的时程，从而影响AP的时程。据我们所知，在正常或病理条件下，MSC与Na+/Ca2+电流的相互作用还没有从实验和理论上进行研究。在拟议的FIRCA项目中，我们将测试转运抑制剂，特别是阻断MSCs的GsMTx-4肽，以及钙通道调节剂(作为Na+/Ca2+电流阻滞剂)对小梁和乳头肌一维标本的收缩、动作电位构型和细胞内钙动力学的影响。为了预测实验结果的细胞内机制，我们将建立等电势细胞的数学模型，并阐明MSCs在心律紊乱的起源中的作用及其相对贡献。在整个心脏中，机械应变在收缩过程中的分布在机电功能中起着关键作用。因此，我们的下一个目标是建立心肌组织的一维和二维数学模型(虚拟支架)，并探索变形诱导的应力/应变场对虚拟组织的机电响应和钙动力学的影响。俄罗斯团队在研究心肌的机械活动方面有很好的专业知识，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不同肌肉负荷和动态变形模式下肌肉收缩过程中肌力和长度的时间过程以及钙动力学和电活动。我们将利用俄罗斯的专业技术进行进一步的模型开发，以研究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.