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（由申请人提供）：心力衰竭（HF）是一种令人衰弱的疾病，预后不良。通过心脏G蛋白G的过量信号？亚基是HF病理生理学的重要组成部分。他们将胞质G蛋白偶联受体激酶2（GRK2，BARK1）募集到HF中刺激的B-ARS的水平升高，从而导致慢性B-AR脱敏和下调HF的标志。以前的数据表明抑制G？信号传导及其与GRK2的相互作用在HF中可能具有治疗值。我们最近开发了一种新型的小分子靶向策略，以选择性地抑制G？结合相互作用，并确定了几个g？小分子抑制剂（Bonacci等，Science，2006）。特别是，在结构和功能上基本相同的化合物M119和Gallein可以阻止G？ -grk2体外相互作用。我们的初步数据进一步表明，它们减少了GRK2膜的募集，增强的腺苷酸环化酶活性，并响应BAR激动剂而分离的成年心肌细胞中的收缩力增加。在体内，急性药理HF模型中的全身性递送标准化心脏功能，形态和GRK2表达。重要的是，每天治疗一个月，当用已建立的HF给小鼠施用HF和病理心脏重塑的进展。最近的数据表明，肾上腺G升高？ HF中的-grk2信号传导导致肾上腺肾上腺儿茶酚胺释放的肾上腺A2-AR反馈抑制。这些数据表明，同时抑制心脏和肾上腺G？ -grk2信号传导在HF中可能具有很大的治疗益处。病理心脏G ??最近发现信号与T188的新型ERK1/2磷酸化相互作用并导致持续的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？，唯一的g？ - 受监管的PI3K。任何一个PI3K的大肽破坏了？活动还是PI3K？与GRK2的互动及其招募到G？也已知在HF模型中将2-AR信号传导和心脏功能归一化。我们现在已经确定了特定的G？抑制性化合物可以阻止G？与grk2，pi3k？或两者的相互作用。我们的总体假设是选择性的小分子靶向G？在心脏和肾上腺中，是HF的新型治疗范式，并且是一般和选择性的G？化合物将增强我们当前对病理G的理解？心脏发出信号。为了解决这一假设，我们提出以下特定目的：1）确定小分子G的功效和心脏特异性？ HF手术模型的抑制作用。 2）确定小分子g的肾上腺作用？ HF的抑制作用。 3）确定G的作用？与新型ERK1/2途径，GRK2或PI3K的相互作用？在病理心脏信号，肥大和心肌细胞收缩性中。总而言之，我们拥有令人兴奋的初步数据，以识别选择性，生物利用g？抑制性化合物可防止HF和HALT HF进展。该提案中概述的实验可以为HF提供新颖的治疗策略。

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。