Stress-activated Map Kinases in Heart Failure

描述（由申请人提供）：心力衰竭是美国最重要的健康问题之一，缺血/心肌梗死是其主要原因之一。促炎基因，包括TNF α，IL-6和COX 2是高度诱导的，并被认为有助于缺血/再灌注损伤后心力衰竭的病理性代偿失调。然而，介导其在心肌细胞中诱导的信号传导机制尚未完全建立。在我们的初步研究中，我们发现应激激活的丝裂原活化蛋白（MAP）激酶p38的激活与缺血/再灌注高度相关。靶向激活p38活性导致诱导心肌细胞中的促炎基因和完整心脏中的病理性重构。这些发现导致我们目前的假设，p38 MAP激酶激活有助于特定方面的心脏病理缺血/心肌梗死通过靶向调节心肌细胞中的应激反应基因和炎症细胞因子。在本研究中，我们将通过以下3个具体目标来严格验证这一假设：1）确定p38在体内调节炎症基因诱导和心脏重塑中的功能作用。2）探讨p38通路在心肌梗死后炎症基因诱导和心肌损伤中的生理作用。3)探讨p38在心肌细胞中的功能和调控的分子基础。这些目标的实现将有助于阐明p38通路在缺血性心力衰竭中的功能意义，并为心力衰竭病理性重构的分子机制提供新的见解。更重要的是，p38信号通路作为一个潜在的新的治疗靶点，治疗心肌梗死和缺血性心力衰竭提供了重要的信息。

DESCRIPTION (provided by applicant): Heart failure is one (1) of the most significant health issues in the US with ischemia/myocardial infarct as one (1) of its leading causes. Pro-inflammatory genes, including TNFalpha, IL-6 and COX2 are highly induced and thought to contribute to pathological decompensation in heart failure following ischemia/reperfusion injury. However, the signaling mechanism mediating their induction in cardiomyocytes is not yet well established. In our preliminary studies, we find that activation of stress-activated mitogen activated protein (MAP) kinase, p38 is highly correlated with ischemia/reperfusion. Targeted activation of p38 activities leads to induction of pro-inflammatory genes in cardiomyocytes and pathological remodeling in intact heart. These findings lead to our current hypothesis that p38 MAP kinase activation contributes to specific aspects of cardiac pathology during ischemia/myocardial infarction via targeted regulation of stress-response genes and inflammatory cytokine in cardiomyocytes. In this proposal, we will rigorously test this hypothesis by achieving the following 3 specific aims: 1) To determine the functional role of p38 in regulating inflammatory gene induction and cardiac remodeling in vivo. 2).To determine the physiological role of p38 pathway in inflammatory gene induction and cardiac injury following myocardial infarction. 3) To determine the molecular basis of p38 function and regulation in cardiomyocytes. Accomplishing these aims will establish the functional significance of p38 pathway in ischemic heart failure and add important new insight to the molecular mechanisms of pathological remodeling in failing heart. More importantly, it will provide critical information about p38 pathway as a potential new therapeutic target to treat myocardial infarction and ischemic heart failure.