Abnormal intracellular calcium release in heart failure

 描述(申请人提供)：心力衰竭(HF)是一种日益流行的疾病，当心肌无法维持足够的心输出量时发生。心力衰竭患者的发病率和死亡率增加，死亡原因为心脏机械功能进行性衰竭(泵衰竭)或室性心律失常。心脏病理结构重构与心肌细胞肥大和/或死亡相关，是心衰的共同特征。心脏兰尼定受体(RyR2)功能失调引起的肌浆网(SR)钙释放的改变(即RyR2的泄漏)与心衰时的收缩功能障碍和心律失常以及心功能衰竭的结构重构有关。事实上，调节失调的RyR2促进了心衰，而RyR2在心衰过程中的调节也越来越失调。在心力衰竭期间，自主神经系统的平衡发生变化，出现副交感神经收缩和交感神经过度。交感神经系统过度信号作为RyR2功能障碍的中介物的作用已经明确。然而，副交感神经系统作为RyR2功能和功能障碍的中介的潜在作用尚不清楚。迷走神经(副交感神经)刺激治疗心力衰竭的研究显示前景看好。然而，增强迷走神经对心脏刺激的潜在益处的机制尚不清楚。这项建议的主要目的是明确副交感神经刺激在正常和衰竭心脏中的后果和潜在机制，以及在心力衰竭中副交感神经增强/迷走神经刺激有益效果的基础因素。我们建议1)明确副交感神经系统对心室肌钙循环的调节作用和机制；2)确定毒鼠碱对衰竭心脏心肌细胞钙调节的模式和机制，并测试通过副交感神经增强来改善心衰心肌细胞钙调节的治疗潜力。除了临床前验证的心力衰竭模型外，还将使用遗传学和药理学方法的组合。我们提出了一种结合先进和最先进的生物化学(如蛋白质磷酸化)、细胞生理学(多隔室和高分辨率2D钙成像)和生物物理方法(单次RyR2记录)的系统集成方法。所获得的信息将提供机械信息，可用于通过操纵副交感神经系统来优化改善心脏功能的策略。

 DESCRIPTION (provided by applicant): Heart failure (HF) is an increasingly prevalent disease that occurs when the cardiac muscle is unable to maintain a sufficient cardiac output. HF patients experience increased morbidity and mortality with death resulting from progressive failure of cardiac mechanical function (pump failure) or ventricular arrhythmias. Pathological structural remodeling of the heart associated with myocyte hypertrophy and/or death is a common feature of HF. Altered Ca release from the sarcoplasmic reticulum (SR) due to deregulated cardiac ryanodine receptor (RyR2) function (i.e. "leaky RyR2s") has been implicated in both contractile dysfunction and arrhythmias in HF as well as in the structural remodeling of the failing heart. Indeed, dysregulated RyR2s contribute to HF, and RyR2s are increasingly dysregulated during HF. During HF, autonomic nervous system balance shifts such that there is parasympathetic withdrawal and sympathetic excess. The role of the excess sympathetic nervous system signaling as a mediator of RyR2 dysfunction is clearly established. However, the potential role of the parasympathetic nervous system as a mediator of RyR2 function and dysfunction is unclear. Investigations with vagal (parasympathetic) stimulation have shown promise in treating HF. However the mechanisms for potential benefit of augmenting vagal stimulation to the heart are unknown. The main goal of this proposal is to define the consequences and the underlying mechanisms of parasympathetic stimulation in normal and failing hearts as well as the factors that underlie the beneficial effects of parasympathetic augmentation/vagal stimulation in HF. We propose to 1) Define the role and mechanisms of ventricular Ca cycling modulation by the parasympathetic nervous system; and 2) Determine the modes and mechanisms of muscarinic modulation of myocyte Ca handling in the failing heart and test the therapeutic potential of improved Ca handling via parasympathetic augmentation in HF. A combination of genetic and pharmacologic approaches will be used, in addition to a pre-clinical validated HF model. We propose a systematic integrated approach using a combination of advanced and state-of-the-art biochemical (e.g. protein phosphorylation), cell physiology (multicompartment and high resolution 2D Ca imaging) and biophysical methods (single RyR2 recordings). Information gained will provide mechanistic information that could be used in the optimization of strategies to improve cardiac function through manipulation of the parasympathetic nervous system.