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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

基本信息

批准号：
8450792
负责人：
Burns C Blaxall
金额：
$ 36.05万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-05 至 2015-05-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450792
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 MAPK3 gene 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

项目摘要

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.

描述(申请人提供)：心力衰竭(HF)是一种预后不佳的衰弱疾病。心脏G蛋白G的过度信号？？亚基是心衰病理生理学的重要组成部分。在心力衰竭中，它们将高水平的胞浆G蛋白偶联受体激酶2(GRK2，bARK1)招募到激动剂刺激的b-AR，导致慢性b-AR脱敏和下调，这是心力衰竭的特征。此前的数据表明，抑制G？信号转导及其与GRK2的相互作用可能在心力衰竭中具有治疗价值。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等人，《科学》，2006年)。特别是，化合物M119和Gallein在结构和功能上基本相同，在体外被发现可以阻断G？-GRK2的相互作用。我们的初步数据进一步表明，它们减少了GRK2膜的募集，增强了腺苷环化酶的活性，并增加了b-AR激动剂对分离的成年心肌细胞的收缩能力。在体内，在急性药理性心衰模型中，全身给药使心功能、心形态和GRK2表达正常化。重要的是，每天治疗一个月可以阻止心力衰竭的进展和病理性心脏重塑，当给予已经确定的心力衰竭的小鼠。最近的数据表明，肾上腺G？？-GRK2信号在心力衰竭时升高，导致肾上腺α2-AR反馈抑制肾上腺儿茶酚胺释放的脱敏。这些数据表明，同时抑制心脏和肾上腺G？？-GRK2信号可能对心力衰竭有显著的治疗效果。病理性心脏G？？最近发现信号与T188上新的、持续的ERK1/2磷酸化相互作用，并导致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，PI3K？是唯一受G？？调节的PI3K。PI3K？活动还是PI3K？与GRK2的互动以及他们招募到G？？在心力衰竭模型中也能使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？或两者都进行交互。我们的总体假设是选择性小分子靶向G？心脏和肾上腺是治疗心力衰竭的一种新的治疗模式，而这种普遍的和选择性的G？化合物将增强我们目前对病理性G？在内心发出信号。为了解决这一假设，我们提出了以下具体目标：1)确定小分子G？？心衰手术模型中的抑制作用。2)确定小分子G？？肾上腺的作用。在HF中抑制。3)确定G？？与新的ERK1/2途径相互作用--GRK2或PI3K？在病理性心肌信号传导中，肥大与心肌细胞收缩功能密切相关。总而言之，我们有令人兴奋的初步数据来确定选择性的、生物可用的G？？既能预防心力衰竭又能阻止心力衰竭进展的抑制性化合物。这项提案中概述的实验可能为心力衰竭提供一种新的治疗策略。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension.

DOI：
10.1161/circulationaha.112.109868
发表时间：
2012-12-11
期刊：
Circulation
影响因子：
37.8
作者：
Piao L;Fang YH;Parikh KS;Ryan JJ;D'Souza KM;Theccanat T;Toth PT;Pogoriler J;Paul J;Blaxall BC;Akhter SA;Archer SL
通讯作者：
Archer SL

Atrioventricular heart block and syncope coincident with diagnosis of systemic lupus erythematosus.

房室传导阻滞和晕厥符合系统性红斑狼疮的诊断。