RGS Regulation of Cardiac Signaling and Hypertrophy

RGS 对心脏信号传导和肥厚的调节

• 批准号: 7619985
• 负责人: Ulrike Mende
• 金额: $ 36.41万
• 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/7619985
• 关键词: Address; Attenuated; Biological; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Surface Receptors; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Development; Down-Regulation; Event; Exercise; Feedback; Financial compensation; G Protein-Coupled Receptor Signaling; GTP-Binding Protein Regulators; Goals; Growth; Heart; Heart failure; Heterotrimeric GTP-Binding Proteins; Homeostasis; Hypertrophy; Internet; Left Ventricular Hypertrophy; Light; Mediating; Modeling; Molecular; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Phenotype; Phosphorylation; Physiological; Property; Proteins; RGS Proteins; RGS2 gene; RNA Interference; Regulation; Reporting; Research Personnel; Role; Signal Pathway; Signal Transduction; Stream; Stress; Testing; Therapeutic; Therapeutic Intervention; Transgenic Organisms; Translations; Ventricular; Ventricular Remodeling; Workload; base; cardiovascular risk factor; conditioning; gain of function; hemodynamics; hormone sensitivity; in vivo; inhibitor/antagonist; insight; loss of function; mortality; novel; outcome forecast; overexpression; postnatal; pressure; programs; research study; response; restraint; therapeutic target

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）：心肌生长是心肌对大量生理和病理生理条件引起的血液动力学载荷条件改变的反应。肥大的生长是由复杂的互连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，信号传导机制的激活/失活的差异可以解释各种肥大形式的表型和预后的差异。虽然最初是功能性的补偿（尽管不是必需的）补偿，但响应过量血液动力学工作量而持续的肥大通常会导致心室重塑，功能失调和明显心力衰竭的发展。通过异三聚体GQ/11蛋白质从细胞表面受体到细胞内效应子的增强信号转导，众所周知，它们会集中参与肥大的发展。 GQ/11信号传导由G蛋白信号传导（RGS）的调节剂集成，这些调节剂是跨膜信号持续时间和激素灵敏度的负调节剂。初步数据导致了以下中央假设：（1）RGS2是心脏GQ/11信号传导和肥大的重要负调节剂。 （2）通过进一步增强GQ/11信号传导，RGS2的下调与肥大发育至关重要。 （3）增强的GQ/11信号及其有害效应可以通过增加RGS2的量/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介导了CGMP诱导的抗神经性效应。这些假设将在以下特定目的中使用增益和功能丧失方法进行检验：（1）描绘内源性RGS2在调节分离的心室心肌细胞中GQ/11介导的信号传导和肥大中的功能作用。 （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磷酸化是否增强其对GQ/11信号传导的抑制作用，从而在CGMP和GQ/11信号之间提供串扰。越来越多地认识到，调节肥大的负调节剂可能成为心力衰竭治疗的重要策略，因为它试图模仿负面反馈机制，这些反馈机制通常是维持细胞稳态的核心，这些机制定义了RGS2对心脏信号和功能的生物学作用，并将其与调节性的范围相结合，以使其与范围内的影响相结合，从而可以触发性能，从而可以触发性能。针对微调GQ/11信号传导（即，在靶向不良适应性的同时保留理想的特征），以调整RGS2的活性和/或量来实现适应不良的特征。