Exploring a Role for beta-Arrestins in Cardiac Injury and Repair

描述(申请人提供)：由于心力衰竭(HF)的特征仍然是生活质量下降和高死亡率，继续努力阐明分子病理机制作为开发新疗法的基础是至关重要的。缺血性损伤后的心肌损伤在很大程度上促进了慢性心力衰竭综合征的发展。赞助商的实验室(Walter J.Koch博士)已经确定G蛋白偶联受体(GPCRK)-2(GRK2)在受损和应激心肌的病理生理学中起关键作用。经典的认识是，GRK2磷酸化激动剂激活的GPCRs，如心脏中的b-肾上腺素能受体(BAR)，触发脱敏过程。终止GPCR信号之后是b-arrestins的募集，这导致G蛋白与受体的物理解偶联。有趣的是，作用于GRK活性下游的b-arrestins也可以通过新的激酶支架功能启动细胞内信号通路，而不依赖于G蛋白信号。在过去的二十年里，Koch实验室的重点一直是研究心肌细胞中受脱敏机制调控的受体后信号。更具体地说，该实验室主要关注GRK，但现在是研究b-拦阻蛋白的作用的时候了，因为很明显，它们是G蛋白非依赖性信号的新调节者。由于交感神经系统似乎在干细胞从骨髓中排出的过程中起着关键作用，我们感兴趣的是肾上腺素能信号调节如何通过再生机制影响缺血心肌的修复，以及b-拦截素如何延缓缺血后的损伤过程。因此，这项提议的目的是发现b-拦阻蛋白在心肌缺血损伤和修复中的新作用。重要的是，初步数据表明，b-arrestins参与了骨髓来源的心脏祖细胞的生长和功能。因此，探讨b-受体阻滞素在心脏损伤和修复中的作用显得尤为重要。

DESCRIPTION (provided by applicant): As heart failure (HF) continues to be characterized by diminished quality of life and high mortality rate, it is crucial to continue our efforts to elucidate molecular pathological mechanisms as a basis for the development of novel therapies. Myocardial injury after an ischemic insult contributes largely to the development of the chronic HF syndrome. The sponsor's (Dr. Walter J. Koch) laboratory has identified a key role for G protein- coupled receptor (GPCR) kinase-2 (GRK2) in the pathophysiology of injured and stressed myocardium. It is classically known that GRK2 phosphorylates agonist activated GPCRs, such as b-adrenergic receptors (bARs) in the heart, triggering the process of desensitization. Termination of GPCR signaling is followed by the recruitment of b-arrestins, which leads to physical uncoupling of the G protein from the receptor. Interestingly, b-arrestins, acting downstream of GRK activity, can also initiate intracellular signaling pathways through novel kinase scaffolding functions and independently of G protein signaling. The focus of the Koch laboratory over the last two decades has been studying post-receptor signaling regulated by the desensitization machinery in cardiac myocytes. More specifically, the lab has mainly focused in GRKs but it is timely to investigate the role of b-arrestins since it is clear they are novel regulators of G protein-independent signaling. Since the sympathetic nervous system appears to play a key role in stem cells egress from the bone marrow, we are interested in how adrenergic signaling regulation may affect repair of ischemic myocardium through regeneration mechanisms in addition to how b-arrestins may later the injury process after ischemia. Therefore, the goal of this proposal is to discover novel roles for b-arrestins in myocardial ischemic injury and repair. Importantly, preliminary data suggests involvement of b-arrestins in bone marrow-derived cardiac progenitor cell growth and function. Therefore, it appears significant to address the role of b-arrestins in cardiac injury and repair.