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.
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