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。肥厚生长是由错综复杂的相互关联的信号通路网络触发的，涉及多个分子水平的控制。信号机制激活/失活的差异通常被认为可以解释不同形式的肥大在表型和预后上的差异。虽然最初是一种功能性代偿（尽管不是必需的），但过度血流动力学负荷引起的持续肥厚往往导致心室重构，伴有功能性代偿失代偿，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器的增强信号转导被广泛认为是肥厚发育的中心参与。Gq/11信号是由G蛋白信号调节因子（regulatory of G protein signaling， RGS）整合的，RGS是跨膜信号持续时间和激素敏感性的负调控因子。初步数据得出以下中心假设：(1)RGS2是心脏Gq/11信号传导和肥厚的重要负调控因子。(2) RGS2的下调通过进一步增强Gq/11信号通路，在肥厚发育中起着至关重要的作用。(3) Gq/11信号的增强及其有害影响可以通过增加RGS2的数量或功能来缓解。(4)最近有证据表明RGS2是蛋白激酶G的下游靶点，我们进一步假设心脏RGS2介导cgmp诱导的抗肥厚作用。这些假设将在以下具体目标中使用功能增益和功能损失方法进行验证：(1)描述内源性RGS2在调节Gq/11介导的信号传导和体内分离心室心肌细胞和完整心脏肥厚中的功能作用。(2)为了确定有条件的、心脏特异性的RGS2表达是否可以减轻Gq/11介导的肥厚，同时保持心脏适应需求增加的能力。(3)确定pkg诱导的RGS2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信号之间提供串扰。越来越多的人认识到，调节肥厚的负调节因子可能成为心力衰竭治疗的重要策略，因为它试图模仿负反馈机制，而负反馈机制通常是维持细胞稳态的核心。定义RGS2在心脏信号传导和功能中的生物学作用，结合其调节特性如何被利用来调节心脏肥厚反应的见解。可以通过调节RGS2的活性和/或数量，形成旨在微调Gq/11信号的治疗干预的基础（即，在保留理想特征的同时靶向那些不适应的特征）。

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.