Monomeric G-proteins and Cardioprotection from Heart Failure

 描述（由申请人提供）：单体G蛋白和抗心力衰竭药物保护美国心力衰竭的发病率随着年度费用的增加而稳步增加 超过300亿美元，预计从现在到2030年，成本将增加127%。射血分数降低的心力衰竭（HFrEF）发生在约45%的HF患者中，与射血分数保留的HF相比，其生存期更长;然而，治疗选择较差，仅限于增加生存期而不改善收缩功能。诸如β-受体阻滞剂的药剂延长HFrEF的寿命（不一定是生活质量）的成功将注意力从HFrEF中心脏缺陷是不能以足够的力收缩以满足需求的基本原理上移开。这一新的建议是由我们的发现，一种新的心脏表型所造成的删除Rad-GTdR。Rad-null小鼠（Rad-/-）表现出增加的心脏收缩力，持续到衰老，并表现出年龄和性别匹配的动物。Rad-/-小鼠还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。在这个建议中，我们将测试两类潜在相关但相互排斥的机制假设。首先，我们将评估Rad消融后Ca 2+稳态改变的贡献;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。三个相辅相成的目标指导我们的研究。首先，我们将测试的假设，镭消融赋予增强功能，通过肌膜钙离子内流。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缺失通过增强细胞内Ca 2+同步性和保护β-AR信号传导而有助于心脏保护的假设。再次，心脏结构和功能的评估将跨越从分子到细胞到器官水平和体内功能的尺度。我们的第三个目标集中在Rad-deletion作为一种潜在的有益的治疗方法。总的来说，该提案测试了增强心脏功能的新机制，该机制赋予心脏保护以对抗持续的压力过载和慢性应激信号。

 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.