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.

单体 G 蛋白和心力衰竭的心脏保护作用美国心力衰竭发病率稳步上升，每年造成的费用超过 300 亿美元从现在到 2030 年，费用预计将增加 127%。射血分数降低的心力衰竭 (HFrEF) 发生在约 45% 的心力衰竭患者中，与保存完好的心力衰竭患者相比，与更长的生存期相关然而，射血分数的治疗方案很差，并且仅限于提高生存率而无法改善收缩功能。诸如 β 阻滞剂等药物成功地延长了患者的寿命（不一定是生活质量）。 HFrEF 引起人们对 HFrEF 的基本原则的关注，即 HFrEF 的心脏缺陷是无法收缩具有足够的力量来满足需求。这项新提案的动机是我们对一种新型心脏的发现。 Rad-GTPase 缺失引起的表型 (Rad-/-) 显示出心肌收缩力增加。还显示，这种现象在衰老过程中仍能很好地持续，并且表现优于年龄和性别匹配的动物。针对慢性儿茶酚胺刺激和慢性压力超负荷的心脏保护作用。建议我们将测试两类潜在相关但相互排斥的机制假设。将评估 Ca2+ 稳态改变对 Rad 消融的影响；其次，我们将评估 Rad 对 -肾上腺素能受体 (-AR) 信号轴的贡献三个互补目标指南。首先，我们将检验放射消融通过肌膜增强功能的假设。这些实验将涵盖从分子到整个心脏的功能范围。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 缺失通过增强细胞内 Ca2+ 同步性和 -AR 信号传导的保存。再次，评估心脏结构和功能。功能将跨越从分子到细胞、到器官水平和体内功能的各个层面。总体而言，该提案测试了一种新颖的方法，即消除放射线作为一种潜在有益的治疗方法。增强心脏功能的机制，可针对持续压力提供心脏保护超负荷和慢性压力信号。