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

描述（由申请人提供）：由于心力衰竭（HF）一直以生活质量下降和高死亡率为特征，因此继续努力阐明分子病理机制作为开发新疗法的基础至关重要。缺血性损伤后的心肌损伤在很大程度上促进了慢性心衰综合征的发展。发起人Walter J. Koch博士的实验室已经确定了G蛋白偶联受体（GPCR）激酶-2 （GRK2）在损伤和应激心肌病理生理中的关键作用。众所周知，GRK2会磷酸化激动剂激活的gpcr，如心脏中的b-肾上腺素能受体（bar），从而触发脱敏过程。GPCR信号的终止伴随着b-阻滞蛋白的募集，这导致G蛋白与受体的物理解偶联。有趣的是，b-arrestins作用于GRK活性的下游，也可以通过新的激酶支架功能启动细胞内信号通路，独立于G蛋白信号传导。在过去的二十年里，科赫实验室的重点一直是研究由心肌细胞脱敏机制调节的受体后信号。更具体地说，该实验室主要关注grk，但现在研究b-阻滞蛋白的作用是及时的，因为很明显它们是G蛋白非依赖性信号传导的新型调节剂。由于交感神经系统似乎在干细胞从骨髓输出中起关键作用，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-抑制素如何延缓缺血后的损伤过程。因此，本研究的目标是发现b-骤停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-骤停蛋白参与骨髓源性心脏祖细胞的生长和功能。因此，解决b-骤停在心脏损伤和修复中的作用显得很重要。

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. PUBLIC HEALTH RELEVANCE: Considering escalating numbers of individuals experiencing diminished quality of life and high morbidity rate due to heart failure, it is of paramount importance to continue our efforts to understand the underlying pathological mechanisms of the syndrome. In this study, we propose to investigate the scaffolding and signaling proteins b-arrestin1 and b -arrestin2 and their involvement in the repair and regeneration of the injured myocardium. Additionally, we will investigate their role in cardiac stem and progenitor cell activation, with hopes to contribute to the development of novel treatments.