SD COBRE: P21-ACTIVATED KINASE (PAK) SIGNALING IN HYPERTROPHY AND HEART FAILURE

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall theme of this proposal is to gain new insight into the molecular mechanisms that control cardiac hypertrophic growth and heart failure. The efficacy of currently available therapeutic options for cardiac hypertrophy and heart failure is limited largely because the underlying molecular signaling mechanisms remain obscure. The p21-activated kinase (PAK) is a serine/ threonine protein kinase that is activated by a variety of external stimuli that act through various cell surface receptors including G protein-coupled receptors and receptor tyrosine kinases. Upon activation, PAK can modulate the activities of multiple intracellular signaling pathways including various mitogen-activated protein (MAP) kinases that have been shown to regulate important pathophysiological processes in the heart such as hypertrophy and apoptosis. Thus, PAK appears to be positioned at a converging point in the intracellular signaling network that integrates signals from cell surface receptors and then relays them to downstream effectors. Our preliminary data show that PAK is activated in cardiomyocytes by multiple hypertrophic stimuli both in vitro and in vivo, supporting a role of PAK in the cardiac hypertrophic response. This project will test the central hypothesis that p21-activated kinase (PAK) is a critical mediator of cardiac hypertrophic growth. This will be accomplished by the following specific aims: (1) To determine if PAK is sufficient to induce cardiac hypertrophy in vitro and in vivo. This aim will test the hypothesis that increased PAK activity is able to cause cardiac hypertrophic growth. (2) To test the necessity of PAK signaling in cardiac hypertrophy. The underlying hypothesis is that PAK signaling is required for an effective hypertrophic response. (3) To explore the possible mechanisms whereby PAK modulates the cardiac hypertrophic response. This aim is to test the hypothesis that PAK regulates cardiac hypertrophy by interacting with specific down stream effectors. The experiments to be carried out in the proposed studies will define if PAK is an important mediator of cardiac hypertrophy, thus, a potential target for the development of novel strategies for the treatment of cardiac hypertrophy and heart failure.