RGS Regulation of Cardiac Signaling and Hypertrophy

RGS 对心脏信号传导和肥厚的调节

• 批准号: 7094798
• 负责人: Ulrike Mende
• 金额: $ 39.63万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094798
• 关键词: G protein; biological signal transduction; cGMP dependent protein kinase; cardiac myocytes; cell growth regulation; enzyme activity; gene expression; genetically modified animals; heart enlargement; heart ventricle; laboratory mouse; laboratory rat; mature animal; newborn animals; pathologic process; phosphorylation; protein structure function; tissue /cell culture; ventricular hypertrophy

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.

描述（由申请人提供）：心肌生长是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条件改变的反应。肥大性生长是由相互关联的信号通路的复杂网络触发的，并涉及多个分子水平的控制。人们普遍认为信号机制激活/失活的差异可以解释各种形式的肥大之间表型和预后的差异。虽然最初是功能性（尽管不是必需的）代偿，但由于血流动力学负荷过多而导致的持续性肥大常常导致心室重塑，伴有功能性失代偿和明显心力衰竭的发展。人们普遍认为，通过异三聚体 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在肥大发展中发挥着重要作用。 Gq/11 信号传导由 G 蛋白信号传导调节器 (RGS) 整合，这些调节器是跨膜信号持续时间和激素敏感性的负调节器。初步数据得出以下中心假设：（1）RGS2是心脏Gq/11信号传导和肥大的重要负调节因子。 (2) RGS2 的下调通过进一步增强 Gq/11 信号传导而与肥大的发展密切相关。 (3) 增强的 Gq/11 信号传导及其有害影响可以通过增加 RGS2 的数量/功能来减轻。 (4) 鉴于最近的证据表明 RGS2 是蛋白激酶 G 的下游靶标，我们进一步假设心脏 RGS2 介导 cGMP 诱导的抗肥厚作用。这些假设将使用功能获得和功能丧失的方法进行测试，具体目标如下：(1) 描述内源性 RGS2 在调节离体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体内。 (2) 确定 RGS2 的条件性心脏特异性表达是否可以减弱 Gq/11 介导的肥大，同时保留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。人们越来越认识到，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，因为它试图模仿负反馈机制，而负反馈机制通常对于维持细胞稳态至关重要。深入了解如何利用其调节特性来调节心脏肥厚反应，可能构成旨在微调 Gq/11 信号传导的治疗干预的基础（即，在针对那些适应不良）通过调整 RGS2 的活性和/或数量。