Targeting of B-AR/GBy signaling in the heart with small molecules

用小分子靶向心脏中的 B-AR/GBy 信号传导

• 批准号: 7890141
• 负责人: Burns C Blaxall
• 金额: $ 38.31万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-05 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7890141
• 关键词: ADRBK1 gene; Acute; Address; Adenylate Cyclase; Adrenal Glands; Adult; Agonist; Beta-Adrenergic Receptor Kinase 1; Binding; Bioavailable; Cardiac; Cardiac Myocytes; Catecholamines; Chromaffin Cells; Chronic; Data; Disease; Down-Regulation; Event; Feedback; Functional disorder; G-substrate; GTP-Binding Proteins; Goals; Heart; Heart failure; Hypertrophy; In Vitro; Infection; Membrane; Modeling; Morphology; Mus; Operative Surgical Procedures; Pathologic; Pathway interactions; Peptides; Phosphorylation; Plasma; Prevention; Recruitment Activity; Role; Science; Signal Pathway; Signal Transduction; Specificity; Structure; Surgical Models; Therapeutic; Tissues; Transgenic Organisms; Translational Research; desensitization; gallein; in vivo; inhibitor/antagonist; knockout animal; novel; novel therapeutics; outcome forecast; prevent; public health relevance; research study; response; small molecule

DESCRIPTION (provided by applicant): Heart failure (HF) is a debilitating disease with poor prognosis. Excess signaling through cardiac G-protein G?? subunits is an important component of HF pathophysiology. They recruit elevated levels of cytosolic G-protein coupled receptor kinase 2 (GRK2, bARK1) to agonist-stimulated b-ARs in HF, leading to the chronic b-AR desensitization and down-regulation that are hallmarks of HF. Previous data has suggested that inhibiting G?? signaling and its interaction with GRK2 could be of therapeutic value in HF. We recently developed a novel small molecule targeting strategy to selectively inhibit G?? binding interactions, and identified several G?? small molecule inhibitors (Bonacci et al, Science, 2006). In particular, compounds M119 and gallein, essentially identical in both structure and function, were found to block G?? -GRK2 interaction in vitro. Our preliminary data further demonstrate that they reduce GRK2 membrane recruitment, enhanced adenylyl cyclase activity, and increased contractility in isolated adult cardiomyocytes in response to b-AR agonist. In vivo, systemic delivery normalized cardiac function, morphology and GRK2 expression in an acute pharmacologic HF model. Importantly, daily treatment for one month halted the progression of HF and pathologic cardiac remodeling when administered to mice with established HF. Recent data demonstrates that elevated adrenal G?? -GRK2 signaling in HF leads to desensitization of adrenal a2-AR feedback inhibition of adrenal catecholamine release. These data suggest that simultaneous inhibition of both cardiac and adrenal G?? -GRK2 signaling could be of substantial therapeutic benefit in HF. Pathologic cardiac G?? signaling was recently found to interact with and result in novel, sustained ERK1/2 phosphorylation at T188; this sustained phosphorylation event has been directly associated with HF. Finally, G?? also signals to PI3K?, the only G?? - regulated PI3K. Large peptide disruption of either PI3K? activity or of PI3K? interaction with GRK2 and their recruitment to G?? is also known to normalize 2-AR signaling and cardiac function in HF models. We have now identified specific G?? inhibitory compounds that block G?? interaction with GRK2, PI3K?, or both. Our overall hypothesis is that selective small molecule targeting of G?? in the heart and in the adrenal gland is a novel therapeutic paradigm for HF, and that general and selective G?? compounds will enhance our current understanding of pathologic G?? signaling in the heart. To address this hypothesis, we propose the following specific aims: 1) Determine the efficacy and cardiac specificity of small molecule G?? inhibition in surgical models of HF. 2) Determine the adrenal role of small molecule G?? inhibition in HF. 3) Determine the role of G?? interaction with a novel ERK1/2 pathway, GRK2 or PI3K? in pathologic cardiac signaling, hypertrophy and cardiomyocyte contractility. In summary, we have exciting preliminary data identifying selective, bioavailable G?? inhibitory compounds that both prevent HF and halt HF progression. Experiments outlined in this proposal may provide a novel therapeutic strategy for HF. PUBLIC HEALTH RELEVANCE: Heart failure (HF) is a debilitating disease with poor prognosis. This proposal aims to investigate newly identified bioavailable compounds targeting an established HF pathway. Successful completion of experiments outlined in this proposal will enhance our current understanding of an established HF signaling pathway, and may provide a novel therapeutic strategy for HF.

描述（由申请人提供）：心力衰竭（HF）是一种预后不良的衰弱性疾病。通过心脏G蛋白G传递过量信号？亚基是心衰病理生理的重要组成部分。它们将高水平的胞浆g蛋白偶联受体激酶2 （GRK2, bARK1）募集到HF中激动剂刺激的b-AR，导致慢性b-AR脱敏和下调，这是HF的标志。先前的数据表明，抑制G?？信号通路及其与GRK2的相互作用可能具有治疗HF的价值。我们最近开发了一种新的小分子靶向策略来选择性地抑制G?？结合相互作用，并确定了几个G?？小分子抑制剂（Bonacci et al, Science, 2006）。特别是化合物M119和gallein，在结构和功能上基本相同，被发现阻断G?？-GRK2的体外相互作用。我们的初步数据进一步表明，在b-AR激动剂的作用下，它们减少了GRK2膜募集，增强了腺苷酸环化酶活性，并增加了离体成人心肌细胞的收缩力。在体内，在急性药理学HF模型中，全身递送使心功能、形态学和GRK2表达正常化。重要的是，每天给药一个月可以阻止心衰的进展和病理性心脏重塑。最近的数据表明，肾上腺素G?？HF中的-GRK2信号导致肾上腺a2脱敏- ar反馈抑制肾上腺儿茶酚胺释放。这些数据表明，同时抑制心脏和肾上腺G？-GRK2信号可能对心衰有实质性的治疗益处。病理心脏G?？最近发现信号传导与T188的ERK1/2相互作用并导致新的持续的ERK1/2磷酸化；这种持续的磷酸化事件与HF直接相关。最后,G ? ?也向PI3K发出信号？，唯一的G?？-调节PI3K。PI3K的大肽破坏？还是PI3K的活性？与GRK2的相互作用及其向G?？在HF模型中，也已知能使2-AR信号和心功能正常化。我们现在已经确定了具体的G?？阻断G的抑制性化合物与GRK2， PI3K的相互作用？或者两者兼而有之。我们的总体假设是选择性小分子靶向G?？在心脏和肾上腺中，是HF的一种新的治疗模式，并且一般和选择性G？化合物将增强我们目前对病理性G?？心脏的信号。为了解决这一假设，我们提出以下具体目标：1)确定小分子G?？心衰手术模型的抑制作用。2)确定小分子G?？抑制HF。3)确定G的作用？？与新的ERK1/2通路GRK2或PI3K相互作用？在病理性心脏信号，肥大和心肌细胞收缩。总之，我们有令人兴奋的初步数据确定选择性，生物可利用的G?？抑制性化合物既能预防HF又能阻止HF进展。本文所述的实验可能为心衰提供一种新的治疗策略。