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：
9236730
负责人：
Douglas Allen Andres
金额：
$ 53.38万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9236730
关键词：
ADRBK1 gene Ablation Acute Adrenergic Receptor Age Agonist Animal Model Animals Attention Biological Preservation Cardiac Cardiac Myocytes Catecholamines Chronic Chronic stress Contracts Data Development Disease EFRAC Echocardiography Failure Gender Goals Guanosine Triphosphate Phosphohydrolases Health Heart Heart Abnormalities Heart Hypertrophy Heart failure Homeostasis Hypertrophy Incidence Knockout Mice Laboratories Longevity Magnetic Resonance Imaging Measures Molecular Monomeric GTP-Binding Proteins Mus Myocardial Myocardium Organ Pathologic Pathway interactions Patients Phenotype Quality of life RNA Interference Reducing Agents Regulation Risk Factors Signal Transduction Stress Structure Symptoms System Testing Therapeutic Time Tissues United States Ventricular Remodeling Viral base cost experimental study genetic manipulation heart function improved in vivo innovation molecular scale novel pressure response senescence success

项目摘要

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 in 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.

心力衰竭的单体G蛋白和心脏保护美国的心力衰竭事件正在悄悄地增加，年费用超过300亿美元，并且从现在到2030 （HFREF）发生在约45％的HF患者中，与保留的HF相比，生存期更长射血分数；但是，治疗方案很差，仅限于增加生存率而不改善收缩功能。诸如建筑物之类的代理商的成功延长了寿命（不是必需的生活质量） HFREF将注意力从基本原则中移开，即心脏缺陷是未能收缩有足够的力量满足需求。这个新提案是由我们对新颖心脏的发现的动机由Rad-GTPase缺失引起的表型。 RAD-NULL小鼠（RAD - / - ）显示心脏收缩性增加这持续到感应和表现年龄和性别匹配的动物。 rad - / - 小鼠也显示针对慢性儿茶酚胺刺激和慢性压力超负荷的心脏保护。在这个提案我们将测试两类潜在相关但相互排斥的机械假设。首先，我们将评估改变Ca2+稳态的贡献，以响应RAD消融；第二，我们将评估对肾上腺素能受体（-AR）信号轴的RAD贡献。三个完整的目标指南我们的研究。首先，我们将检验以下假设：rad-ablation供应通过肌符号供应增强的功能 CA2+影响。这些实验将遍历从分子到整个器官的功能尺度。心脏磁共振成像（CMR）和超声心动图也将用于测量体内心脏功能。其次，我们将评估RAD缺失通过增强有助于心脏保护的假设细胞内Ca2+同步和-AR信号的保存。同样，评估心脏结构和功能将遍历从分子到细胞，器官水平和体内功能的范围。我们的第三个目标专注于RAD缺失作为一种潜在的有益疗法方法。总体而言，该提案测试了一本小说心脏功能增强的机制，可以承认心脏保护因持续压力超负荷和慢性应力信号传导。