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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：
9762188
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762188
关键词：
ADRBK1 gene Ablation Acute Adrenergic Receptor Age Agonist Animal Model Animals Arrhythmia Attention Cardiac Cardiac Myocytes Catecholamines Chronic Chronic stress Contracts Data Development Disease EFRAC Echocardiography Failure Gender Goals Growth 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 Receptor Signaling Reducing Agents Regulation Risk Factors Signal Transduction Stress Structure Symptoms System Testing Therapeutic Time Tissues United States Ventricular Remodeling Viral base beta-adrenergic receptor cardioprotection cost experimental study genetic manipulation heart function improved in vivo innovation molecular scale novel preservation pressure receptor function 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 β-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 β-adrenergic receptor (β-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 β-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.

G蛋白单体与心力衰竭的心肌保护美国心力衰竭的发病率稳步增加，每年的费用超过300亿美元，从现在到2030年，成本预计将增加127%。射血分数降低的心力衰竭（HFrEF）发生在约45%的HF患者中，并且与保留的HF相比，与更长的生存期相关射血分数;然而，治疗选择很差，仅限于增加生存率而不改善收缩功能药物（如β受体阻滞剂）延长患者寿命（不一定是生活质量）的成功 HFrEF将注意力从HFrEF中心脏缺陷是无法收缩的基本原则上转移开有足够的力量来满足需求。这项新的建议是由我们发现的一种新的心脏由Rad-GTT基因缺失引起的表型。Rad-null小鼠（Rad-/-）显示心肌收缩力增加它能很好地持续到衰老，并且比年龄和性别匹配的动物表现更好。Rad-/-小鼠也显示对慢性儿茶酚胺刺激和慢性压力超负荷的心脏保护。在这我们将测试两类潜在相关但相互排斥的机制假设。一是将评估Rad消融后Ca 2+稳态改变的作用;其次，我们将评估Rad对β-肾上腺素能受体（β-AR）信号传导轴的贡献。三个互补的目标指南我们的研究首先，我们将测试假设，即Rad-ablation赋予增强功能，通过肌膜 Ca 2+内流。这些实验将跨越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缺失通过增强心肌保护作用的假设。细胞内Ca 2+同步和β-AR信号的保存。再次，评估心脏结构和功能将跨越从分子到细胞到器官水平和体内功能的尺度。我们的第三个目标重点是Rad-deletion作为一种潜在的有益的治疗方法。总的来说，这个提议测试了一部小说，增强心脏功能的机制，对持续压力提供心脏保护超负荷和慢性压力信号。