Stress actvated protein kinases and local structure function in cardiomyocytes

描述(由申请人提供)： 心脏病理性重构信号转导机制的认识 在寻找治疗这种疾病的新疗法方面，失败带来了巨大的希望。应激激活的c-jun氨基末端激酶通路(JNK)被认为与血流动力学应激或心肌损伤所致心力衰竭的发生有关，但其具体功能和潜在机制尚不清楚。虽然JNK与心脏的整体应激反应有关，但项目负责人的初步研究表明，JNK的激活导致缝隙连接处的一种特定和局部的病理，包括局部细胞骨架/膜组织的急剧破坏，连接蛋白43(Cx43)的显著丢失，以及伴随细胞-细胞耦合减弱的Cx43相关细胞骨架蛋白的错误定位。这些观察结果激发了一个令人兴奋的假设，即JNK介导的信号转导是缝隙连接局部病理变化的原因，这是心力衰竭常见表现的一部分。JNK作为一条全球性的应激诱导信号通路，是如何在缝隙连接处导致如此特异性和局部性的病理变化的？因此，全球激活成为局部信号和细胞骨架结构的问题，这是PPG提案的主要主题。利用参与项目之间的协同效应，项目负责人 建议实现以下具体目标：1)确定 JNK激活诱导的膜/细胞骨架结构及其对Cx43的影响 在缝隙连接处的表达和功能。(与项目2合作)；2)确定 蛋白磷酸酶在JNK调控缝隙连接下游信号事件中的作用 蛋白质组织和表达(与项目1合作)；3)补充体外 JNK介导的新的心脏重构过程的研究 建立了时间调控JNK诱导的转基因模型；4)检测 JNK介导的信号对心肌细胞收缩功能的影响(与 项目4)。因此，最先进的计划与其他项目的计划很好地结合在一起。 这个项目旨在提供对连接的基本分子途径的新见解 心脏应激对局部信号和细胞骨架破坏的影响，这是人类心脏病的基础。

DESCRIPTION (provided by applicant): Knowledge of the signaling mechanisms involved in the pathological remodeling in heart failure holds great promise in finding new therapies to treat the disease. Activation of the stressactivated c-Jun N-terminal kinase pathway (JNK) has been implicated in the development of heart failure that results from hemodynamic stress or myocardial injury, yet its specific functions and the underlying mechanisms are still unclear. Although JNK is associated with global stress responses in heart, preliminary studies by the Project Leader indicate that JNK activation leads to a specific and localized pathology at the gap junction, including dramatic disruption of local cytoskeletal/ membrane organization, significant loss of connexin43 (Cx43) and mis-localization of Cx43-associated cytoskeletal protein which accompany diminished cell-cell coupling. These observations motivate an exciting hypothesis that JNK mediated signaling is responsible for the local pathological changes at the gap junction, as part of common manifestations in heart failure. How does JNK, as a global stress-induced signaling pathway, lead to such a very specific and localized pathology at the gap junction? Thus, global activation becomes a problem of local signaling and cytoskeletal structures, the major themes of this PPG proposal. Taking advantage of the synergy among the participating projects, the Project Leader proposes to accomplish the following specific aims: 1) to determine the changes of membrane/cytoskeletal structure induced by JNK activation and the impact on Cx43 expression and function at the gap junction. (Collaboration with Project 2); 2) to determine the role of protein phosphatase in downstream signaling events of JNK in regulating gap junction protein organization and expression (Collaboration with Project 1); 3) to complement the in vitro studies by characterizing the process of JNK mediated cardiac remodeling in a newly established transgenic model with temporally regulated JNK induction; and 4) to determine the impact of JNK mediated signaling on contractile function in heart cells (Collaboration with Project 4). Thus, the state-of-the-art plans are well integrated with those of the other projects. This project is designed to provide new insight into fundamental molecular pathways that link cardiac stress to local signaling and cytoskeletal disruption that underlie human heart disease.