RGS Regulation of Cardiac Signaling and Hypertrophy

说明(申请人提供)：心肌生长是指心肌对由大量生理和病理生理条件引起的血流动力学负荷变化的反应。肥大生长是由相互连接的信号通路组成的错综复杂的网络触发的，涉及多分子水平的控制。信号机制激活/失活的不同通常被认为解释了不同形式的肥厚在表型和预后上的差异。虽然最初是一种功能性(尽管不是必需的)代偿，但由于过度的血流动力学负荷，持续性肥厚往往会导致心室重构和功能失代偿，并发展为明显的心力衰竭。通过异源三聚体GQ/11蛋白从细胞表面受体到细胞内效应分子的信号转导增强是公认的在肥大发生中起中心作用的因素。GQ/11信号是通过G蛋白信号(RGS)调节整合的，RGS是跨膜信号持续时间和激素敏感性的负调节因子。初步数据表明：(1)RGS2是心脏GQ/11信号转导和心肌肥厚的重要负性调节因子。(2)RGS2下调通过进一步增强GQ/11信号通路参与肥大的发生发展。(3)增加RGS2的数量/功能可以减轻GQ/11信号的增强及其有害影响。(4)鉴于最近的证据表明RGS2是蛋白激酶G的下游靶点，我们进一步假设心脏RGS2介导了cGMP诱导的抗肥厚作用。这些假说将通过功能获得和功能丧失的方法来检验，具体目的如下：(1)描述内源性RGS2在调节GQ/11介导的信号和肥大中的功能作用。(2)确定RGS2的心脏特异性条件性表达能否减轻GQ/11介导的心肌肥厚，同时保留心脏适应需求增加的能力。(3)确定PKG诱导的RGS2的磷酸化是否增强了其对GQ/11信号的抑制作用，从而在cGMP和GQ/11信号之间提供了串扰。越来越多的人认识到，调节肥厚的负调控因子可能成为治疗心力衰竭的重要策略，因为它试图模拟负反馈机制，而负反馈机制通常是维持细胞内稳态的关键，定义了RGS2对心脏信号和功能的生物学作用，结合对其调节特性如何被利用来调节心肌肥厚反应的深入了解，可能形成旨在通过调节RGS2的活性和/或数量来微调GQ/11信号的治疗干预的基础(即，保持理想的特征，同时针对那些不适应的)。

DESCRIPTION (provided by applicant): Myocardial growth is a response of the cardiac muscle to altered conditions of hemodynamic load caused by a large number of physiological and pathophysiological conditions. Hypertrophic growth is triggered by an intricate web of interconnected signaling pathways and involves control at multiple molecular levels. Differences in the activation/inactivation of signaling mechanisms are generally believed to explain the differences in phenotype and prognosis among various forms of hypertrophy. While initially a functional (although not essential) compensation, persistent hypertrophy in response to excess hemodynamic workload often leads to ventricular remodeling with functional decompensation and development of overt heart failure. Enhanced signal transduction from cell-surface receptors to intracellular effectors via heterotrimeric Gq/11 proteins is well recognized to be centrally involved in hypertrophy development. Gq/11 signaling is integrated by Regulators of G protein Signaling (RGS) that are negative regulators of transmembrane signal duration and hormone sensitivity. Preliminary data have led to the following central hypotheses: (1) RGS2 is an important negative regulator of cardiac Gq/11 signaling and hypertrophy. (2) Down-regulation of RGS2 is critically involved in hypertrophy development by further enhancing Gq/11 signaling. (3) Enhanced Gq/11 signaling and its deleterious effects can be mitigated by increasing the amount/function of RGS2. (4) In light of recent evidence suggesting that RGS2 is a down-stream target for protein kinase G, we further hypothesize that cardiac RGS2 mediates cGMP-induced anti-hypertrophic effects. These hypotheses will be tested using gain- and loss-of-function approaches in the following Specific Aims: (1) To delineate the functional role of endogenous RGS2 in regulating Gq/11-mediated signaling and hypertrophy in isolated ventricular cardiomyocytes and the intact heart in vivo. (2) To determine whether conditional, cardiac-specific expression of RGS2 can attenuate Gq/11-mediated hypertrophy while preserving the heart's ability to adapt to an increase in demand. (3) To determine whether PKG-induced phosphorylation of RGS2 enhances its inhibitory effect on Gq/11 signaling and thereby provides crosstalk between cGMP and Gq/11 signaling. It is increasingly recognized that modulating negative regulators of hypertrophy could become an important strategy for heart failure treatment, because it attempts to mimic negative feedback mechanisms that are often central for maintaining cellular homeostasis Defining the biological role of RGS2 for cardiac signaling and function, combined with insights into how its regulatory properties could be exploited to modulate cardiac hypertrophic responses, may form the basis for therapeutic interventions aimed at fine-tuning Gq/11 signaling (i.e., preserving desirable features while targeting those that are maladaptive) through adjusting the activity and/or amount of RGS2.