STRESS ACTIVATED MAP KINASES IN HEART FAILURE

心力衰竭（HF）是导致死亡和行动不便的主要原因之一。心衰的发展涉及心肌细胞持续承受各种压力，导致心肌肥厚（CH）、收缩功能丧失和晚期心室扩张。应激激活的MAP激酶（SAPKs）主要由cJun n端激酶（JNK）和p38激酶组成，是多种应激反应的重要信号分子。我们在新生儿心肌细胞中证明，JNK和p38 β活性的激活诱导肥大，p38 α的激活导致细胞死亡。然而，JNK和p38在体内诱导CH和HF的功能尚未确定。因此，本研究的重点是确定JNK和p38通路在心脏肥厚和HF发生中的体内功能，并验证JNK和p38亚型的激活与心脏肥厚、功能障碍和衰竭的特定特征有关的假设。本研究的总体策略是利用高效的基因转移技术和转基因方法特异性操纵小鼠心脏中JNK和p38个体的活性，并通过综合的分子、细胞和生理分析来确定这种操纵对CH和CF发生的影响。具体而言，本研究将实现以下目标：1)。目的：探讨JNK和p38 MAP激酶特异性激活对小鼠心功能和形态的影响。2）. 确定在生理（压力过载）和遗传操作（Ras激活）下，是否需要JNK和p38激活CH和HF的发展。3）. 目的：测定心肌细胞中p38 α和β亚型的体内功能。该研究将广泛而全面地分析JNK和p38在CH和HF发生中的功能作用，涵盖从分子和单细胞到全器官生理的水平。预期的结果将有助于全面了解心衰的机制，并可能最终导致确定更好地治疗这种疾病的新方法。

Heart failure (HF) is one of the leading causes of mortality and immobility. The development of HF involves persistence of various stresses on cardiomyocytes that will lead to cardiac hypertrophy (CH), loss of contractile function and chamber dilation at advanced stage. Stress-activated MAP kinases (SAPKs), mainly consisted of cJun N-terminal kinases (JNK) and p38 kinases, have been implicated as important signaling molecules in a variety of stress responses. We demonstrated in neonatal cardiac myocytes that activation of JNK and p38 beta activities induced hypertrophy and activation of p38 alpha led to cell death. However, the in vivo function of JNK and p38s in the induction of CH and HF has not been established. The focus of this study, therefore, is to determine the in vivo function of JNK and p38 pathways in cardiac hypertrophy and development of HF, and test the hypothesis that activation of JNK and p38 isoforms contributes to specific features of cardiac hypertrophy, dysfunction and failure. The overall strategy for the study is to use efficient gene transfer technique and transgenic approach to specifically manipulate individual JNK and p38 activities in mouse heart, and to determine the effects of such manipulation on the development of CH and CF through comprehensive molecular, cellular and physiological analysis. Specifically, the proposed study will accomplish the following aims: 1). To determine the effects of specific activation of JNK and p38 MAP kinases on cardiac function and morphology in vivo. 2). To determine whether JNK and p38 activation is required in the development of CH and HF under physiological (pressure-overload) and genetic manipulations (Ras activation). 3). To determine the in vivo function of p38 alpha and beta isoforms in cardiac myocytes. The proposed study will provide a broad and comprehensive analysis for the functional roles of JNK and p38s in the development of CH and HF, covering levels from molecular and single cell to whole organ physiology. The expected results will contribute to the overall understanding of the underlined mechanisms of heart failure and may ultimately lead to identification of novel approaches for better treatment of this disease.