Monomeric G-proteins and Cardioprotection from Heart Failure

单体 G 蛋白和心力衰竭的心脏保护作用

基本信息

批准号：
9336423
负责人：
Douglas Allen Andres
金额：
$ 52.5万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336423
关键词：
ADRBK1 gene Ablation Adrenergic Receptor Age Agonist Animal Model Animals Arrhythmia Attention Biological Preservation Cardiac Cardiac Myocytes Catecholamines Chronic Chronic stress Contracts Data Development Disease EFRAC Echocardiography Failure Gender Goals Guanosine Triphosphate Phosphohydrolases Health Hearing Heart Heart Abnormalities Heart Hypertrophy Heart failure Homeostasis Hypertrophy Incidence Injection of therapeutic agent Knockout Mice Laboratories Longevity Magnetic Resonance Imaging Measures Molecular Monomeric GTP-Binding Proteins Mus Myocardial Myocardium Organ Pathway interactions Patients Phenotype Quality of life RNA Interference Receptor Signaling Reducing Agents Regulation Risk Factors Signal Transduction Stress Structure Symptoms System Testing Therapeutic Time Tissues United States Ventricular Remodeling base cost genetic manipulation heart function improved in vivo innovation meetings molecular scale novel pressure research study response senescence success

项目摘要

DESCRIPTION (provided by applicant): Monomeric G-proteins and Cardioprotection from Heart Failure Heart failure incidence in the United States is steadily increasing with annual costs in excess of $30 billion and the cost is expected to increase 127% between now and 2030. Heart failure with reduced ejection fraction (HFrEF) occurs in ~45% of HF patients and is associated with longer survival compared to HF with preserved ejection fraction; however, treatment options are poor and are limited to increasing survival without improving systolic function. Success of agents, such as -blockers, to prolong lifespan (not necessarily quality of life) of HFrEF draws attention away from the fundamental principle that in HFrEF the heart defect is failure to contract with sufficient force to meet demand. This new proposal is motivated by our findings of a novel cardiac phenotype caused by deletion of the Rad-GTPase. Rad-null mice (Rad-/-) show increased cardiac contractility that persists well into senescence and out-performs age- and gender-matched animals. Rad-/- mice also show cardioprotection against chronic catecholamine stimulation, and against chronic pressure overload. In this proposal we will test two classes of potentially related but mutually exclusive mechanistic hypothesis. First, we will evaluate the contribution of altered Ca2+ homeostasis in response to Rad ablation; and second, we will assess Rad contributions to the -adrenergic receptor (-AR) signaling axis. Three complementary Aims guide our studies. First, we will test the hypothesis that Rad-ablation confers enhanced function via sarcolemmal Ca2+ influx. These experiments will traverse scales of function from molecular to whole organ. Cardiac magnetic resonance imaging (CMR) and echocardiography will also be used to measure in vivo heart function. Second, we will evaluate the hypothesis that Rad deletion contributes to cardioprotection via enhancement of intracellular Ca2+ synchrony and preservation of -AR signaling. Again, assessments of heart structure and function will traverse scales from molecular, to cellular, to organ level and i vivo function. Our third aim focuses on Rad-deletion as a potentially beneficial therapeutic approach. Overall, this proposal tests a novel mechanism of augmentation of cardiac function that confers cardioprotection against sustained pressure overload and chronic stress signaling.

描述（由申请人提供）：单体 G 蛋白和心力衰竭的心脏保护作用美国的心力衰竭发病率随着每年的费用而稳步增加超过 300 亿美元，从现在到 2030 年，成本预计将增加 127%。约 45% 的心力衰竭患者发生射血分数降低的心力衰竭 (HFrEF)，与射血分数保留的心力衰竭相比，其生存期更长；然而，治疗选择很差，并且仅限于提高生存率，而无法改善收缩功能。 β-阻滞剂等药物成功地延长了 HFrEF 的寿命（不一定是生活质量）。这一新提议的提出是由于我们发现了 Rad-GTPase 缺失小鼠导致的一种新的心脏表型。 (Rad-/-) 表现出增强的心脏收缩力，这种能力持续到衰老阶段，并且表现优于年龄和性别匹配的动物。我们将测试两类可能相关但相互排斥的机制假设：首先，我们将评估 Ca2+ 稳态改变对 Rad 消融的影响；其次，我们将评估 Rad 对 β-肾上腺素能受体 (β-AR) 的贡献。首先，我们将测试放射消融通过肌膜 Ca2+ 流入增强功能的假设。其次，我们将评估 Rad 缺失通过增强细胞内 Ca2+ 同步性和保存  来促进心脏保护的假设。 -AR 信号传导。对心脏结构和功能的评估将涵盖从分子到细胞、器官水平和体内功能的各个层面。测试了一种增强心脏功能的新机制，该机制可以保护心脏免受持续压力超负荷和慢性应激信号的影响。