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。心力衰竭的发展涉及心肌细胞持续受到各种压力，导致心肌肥大、收缩功能丧失和晚期心腔扩张。应激激活的MAP激酶(SAPKs)主要由cJun氨基末端激酶(JNK)和p38激酶组成，是参与多种应激反应的重要信号分子。我们在新生心肌细胞中证实，激活JNK和p38β活性可导致心肌肥大，激活p38α可导致细胞死亡。然而，JNK和P38S在诱导CH和HF中的体内作用尚未确定。因此，本研究的重点是确定JNK和p38通路在心肌肥厚和心力衰竭发生发展中的体内作用，并验证JNK和p38亚型激活与心肌肥厚、功能障碍和衰竭的特定特征有关的假说。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对小鼠心脏中的JNK和p38活性进行特异性操作，并通过综合的分子、细胞和生理分析来确定这种操作对CH和CF发生的影响。具体地说，拟议的研究将实现以下目标：1)。目的：研究JNK和p38MAPK的特异性激活对心功能和心形态的影响。2)。确定在生理(压力超负荷)和遗传操作(RAS激活)下CH和HF的发生是否需要JNK和p38的激活。3)。目的：研究p38α和β亚型在心肌细胞中的体内功能。这项研究将对JNK和P38S在CH和HF发生中的功能作用提供广泛和全面的分析，涵盖从分子和单细胞到整个器官生理学的水平。预期的结果将有助于全面了解心力衰竭的强调机制，并最终可能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.