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

• 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
• 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

 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(申请人提供)：单体G蛋白和心力衰竭的心脏保护在美国心力衰竭的发病率随着每年的费用稳步增加 超过300亿美元，从现在到2030年，成本预计将增加127%。心力衰竭伴射血分数降低(HFrEF)发生在约45%的心衰患者中，与射血分数保持不变的心衰患者相比，心力衰竭患者的存活时间更长；然而，治疗选择很差，仅限于在不改善收缩功能的情况下增加生存率。阻滞剂等药物的成功延长了高危心脏衰竭的寿命(不一定是生活质量)，从而转移了人们对以下基本原则的关注：在高危高危人群中，心脏缺陷是无法以足够的力量收缩来满足需求。这一新的建议是由我们发现的由Rad-GTP酶缺失引起的一种新的心脏表型引起的。Rad缺失的小鼠(Rad-/-)表现出心肌收缩能力的增加，这种收缩能力一直持续到衰老，表现优于年龄和性别匹配的动物。Rad-/-小鼠还显示出对慢性儿茶酚胺刺激和慢性压力超负荷的心脏保护作用。在这个提案中，我们将测试两类潜在相关但相互排斥的机械论假说。首先，我们将评估Rad消融后改变的钙稳态的贡献；其次，我们将评估Rad对-肾上腺素能受体(-AR)信号轴的贡献。三个相辅相成的目标指导着我们的研究。首先，我们将验证Rad消融通过肌膜钙内流增强功能的假设。这些实验将跨越从分子到整个器官的功能范围。心脏磁共振成像(CMR)和超声心动图也将用于测量活体心脏功能。其次，我们将评估Rad缺失通过增强细胞内钙同步性和保护-AR信号而有助于心脏保护的假说。再一次，心脏结构和功能的评估将跨越从分子到细胞，再到器官水平和体内功能的范围。我们的第三个目标集中在Rad缺失作为一种潜在有益的治疗方法。总体而言，这项建议测试了一种增强心脏功能的新机制，该机制提供了对持续压力超负荷和慢性应激信号的心脏保护。