RGS Regulation of Cardiac Signaling and Hypertrophy

描述（由申请人提供）：心肌生长是心肌对大量生理和病理生理条件引起的血流动力学负荷改变的反应。肥大性生长是由一个错综复杂的相互连接的信号通路网络触发的，涉及多个分子水平的控制。信号传导机制的激活/失活的差异通常被认为可以解释各种形式的肥大之间表型和预后的差异。虽然最初是一种功能性（尽管不是必需的）代偿，但响应于过度血流动力学工作负荷的持续性肥大通常会导致心室重塑伴功能性失代偿和明显心力衰竭的发展。通过异源三聚体Gq/11蛋白从细胞表面受体到细胞内效应物的增强的信号转导被充分认识到是参与肥大发展的中心。Gq/11信号通过G蛋白信号调节子（Regulators of G protein Signaling，RGS）整合，RGS是跨膜信号持续时间和激素敏感性的负调节子。初步的数据已经导致了以下中心假设：（1）RGS 2是心脏Gq/11信号传导和肥大的重要负调节剂。(2)RGS 2的下调通过进一步增强Gq/11信号传导而关键地参与肥大发展。(3)增强的Gq/11信号传导及其有害作用可以通过增加RGS 2的量/功能来减轻。(4)鉴于最近的证据表明RGS 2是蛋白激酶G的下游靶点，我们进一步假设心脏RGS 2介导cGMP诱导的抗肥大作用。这些假设将在以下具体目的中使用功能获得和功能丧失方法进行测试：（1）描述内源性RGS 2在体内调节分离的心室心肌细胞和完整心脏中Gq/11介导的信号传导和肥大中的功能作用。(2)确定RGS 2的条件性心脏特异性表达是否可以减弱Gq/11介导的肥大，同时保持心脏适应需求增加的能力。(3)确定PKG诱导的RGS 2磷酸化是否增强其对Gq/11信号传导的抑制作用，从而提供cGMP和Gq/11信号传导之间的串扰。越来越多的人认识到，调节肥大的负调节因子可能成为心力衰竭治疗的重要策略，因为它试图模拟负反馈机制，该机制通常是维持细胞稳态的核心。可以形成旨在微调Gq/11信号传导的治疗干预的基础（即，保留期望的特征，同时靶向那些适应不良的特征）。

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.