Knowledge of the signaling mechanisms involved in the pathological remodeling in heart failure holds great promise in finding new therapies to treat the disease. Stress on the heart is known to lead to the activation of a specific kinase, cJun N-terminal Kinase (JNK). This kinase has been implicated in cellular signaling that arises in response to global stress such as high blood pressure and cardiac injury. Yet the specific actions of JNK in heart are unclear. Accordingly the goal of this project is to understand how stress-activated kinase cascades, such as JNK, lead to altered cellular structures and contractility and how these changes link to altered Ca2+ handling in cardiac myocytes in the setting of heart failure.
Our investigations have revealed that specific JNK activation in a transgenic mouse model leads to a specific pathology in the specialized connections between cardiac muscle cells, called gap junctions. Thus we are studying an hypothesis that JNK-mediated signaling is responsible for local pathological changes at the gap junction (see Figure). Thus the main goals of this project are to determine the role of JNK in stress induced changes in membrane/cytoskeletal structure and protein expression at the gap junction and to determine the role of protein phosphatases in JNK mediated changes of gap junction protein expression. We will also determine the pathogenic process of JNK mediated cardiac remodeling in vivo. And examine the impact of JNK mediated gap junction defects on contractile function in heart cells. This research is designed to provide new insight into fundamental molecular pathways that link cardiac stress to local signaling and cytoskeletal disruptions that underlie human heart disease.