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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项提案的总体主题是对控制心脏肥大生长和心力衰竭的分子机制有新的认识。目前可用的治疗心肌肥厚和心力衰竭的方案的疗效有限，主要是因为潜在的分子信号机制仍然不清楚。P21激活的蛋白激酶(PAK)是一种丝氨酸/苏氨酸蛋白激酶，通过G蛋白偶联受体和受体酪氨酸激酶等多种外界刺激激活细胞表面。激活后，PAK可以调节多种细胞内信号通路的活性，包括各种丝裂原活化蛋白(MAP)激酶，已被证明调节心脏肥大和细胞凋亡等重要的病理生理过程。因此，PAK似乎位于细胞内信号网络的汇聚点，该网络整合了来自细胞表面受体的信号，然后将它们传递给下游的效应器。我们的初步数据表明，在体外和体内，多种肥大刺激都能激活心肌细胞中的PAK，这支持了PAK在心肌肥大反应中的作用。该项目将检验p21激活的激酶(PAK)是心脏肥大生长的关键介质这一中心假设。这将通过以下具体目的来实现：(1)确定PAK是否足以在体外和体内诱导心肌肥厚。这一目标将检验PAK活性增加能够导致心肌肥厚生长的假设。(2)探讨PAK信号在心肌肥厚中的必要性。潜在的假设是，PAK信号是有效的肥大反应所必需的。(3)探讨PAK调节心肌肥厚反应的可能机制。这一目的是为了验证PAK通过与特定的下游效应器相互作用来调节心肌肥厚的假设。将在拟议的研究中进行的实验将确定PAK是否是心肌肥厚的重要介质，从而成为开发治疗心肌肥厚和心力衰竭的新策略的潜在靶点。

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.