Novel Function and Regulatory Mechanisms of Stress Kinase p38 in Heart

描述(由申请人提供)： 心力衰竭是一种没有有效治疗的流行疾病，在美国是一个重要的未得到满足的医疗需求。作为对病理应激的响应，心脏在分子、细胞和器官水平上经历了深刻的重塑。在之前的研究中，我们和其他人已经证实，应激激活蛋白激酶p38在介导应激状态下心脏的病理变化中发挥着重要作用。我们已经证明，心脏中p38的结构性激活会导致心脏收缩能力的丧失和与促炎细胞因子诱导相关的病理重构。然而，我们也观察到，在慢性应激或衰老下，p38的基因失活会导致生存受损和功能障碍。这一悖论表明，p38介导的信号在心脏的有害和保护机制中扮演着复杂的角色，这对发展p38靶向治疗心力衰竭具有重要意义。为了更好地了解p38信号在心脏中的潜在机制，我们在分子、细胞和功能水平上对p38信号复合体和p38介导的功能进行了广泛的研究。特别是，我们已经证实，自动磷酸化诱导的非典型p38途径受到一种新的相互作用伙伴Hsp90/CDC37复合体的调控。我们还发现，p38活性在心脏代偿性血管重塑中起关键作用，通过旁分泌串扰从心肌细胞到内皮细胞。最后，我们证明了p38下游蛋白激酶MK2在p38诱导的心脏病变中有选择性的作用。这些新的发现导致了我们目前的假设，即p38激活和下游靶点的不同机制有助于p38信号在心脏代偿性和病理性重塑中的特定作用。在目前的提案中，我们计划通过实现以下具体目标来促进我们对p38介导的应激信号的现有知识：1)。确定非典型性p38蛋白在心脏中激活的分子机制及其功能意义。2)。研究在心脏病理重塑过程中p38对心肌细胞和内皮细胞串扰的调节机制。3)。揭示下游激酶MK2在p38介导的心脏应激反应中的功能意义。这些研究将极大地提高我们目前对心力衰竭的疾病机制的认识，并有助于开发更有效的治疗方法。 公共卫生相关性： 应激蛋白激酶p38是应激反应中的重要信号通路。我们的建议将研究p38的一个新的非规范激活途径的分子机制和功能作用，以及它对从心肌细胞到内皮细胞的串扰的影响。这些研究将提高我们目前对心力衰竭疾病机制的理解，并为开发更好的治疗方法提供潜在的见解。

DESCRIPTION (provided by applicant): Heart failure is a prevailing disease without effective treatment and represents a significant unmet medical need in the US. In response to pathological stresses, heart undergoes profound remodeling at molecular, cellular and organ levels. In previous studies, we and others have established that a stress-activated protein kinase, p38 plays a significant role in mediating pathological changes in heart under stress. We have demonstrated that constitutive activation of p38 in hearts leads to loss of contractility and pathological remodeling associated with pro- inflammatory cytokine induction. However, we have also observed that genetic inactivation of p38 leads to impaired survival and dysfunction under chronic stress or ageing. This paradox indicates complex roles for p38 mediated signaling in both deleterious and protective mechanisms in heart which has significant implications in the development of p38 targeted therapy for heart failure. To better understand the underlying mechanisms of p38 mediated signaling in heart, we have performed extensive studies at molecular, cellular and functional levels about p38 signaling complex and p38 mediated function. In particular, we have established that the auto-phosphorylation induced non-canonical p38 pathway is regulated by a novel interacting partner, Hsp90/Cdc37 complex. We have also discovered that p38 activity is critical to compensatory vascular remodeling in heart via paracrine cross-talk from cardiomyocytes to endothelial cells. Finally, we have demonstrated that a well established p38 downstream kinase MK2 has a selective contribution to p38 induced pathological changes in heart. These novel findings lead to our current hypothesis that diverse mechanisms in p38 activation and downstream targets contribute to specific roles of p38 signaling in both compensatory and pathological remodeling in heart. In the current proposal, we plan to advance our current knowledge of p38 mediated stress signaling by accomplishing the following specific aims: 1). Determine the molecular mechanism and the functional significance of non-canonical p38 kinase activation in heart. 2). Characterize the mechanisms underlying p38 mediated regulation of cardiomyocyte and endothelium cross-talk during pathological remodeling of heart. 3). Uncover the functional significance of downstream kinase MK2 in p38 mediated stress-response in heart. These studies will significantly advance our current knowledge in the disease mechanisms of heart failure and help to develop more effective therapy for the disease. PUBLIC HEALTH RELEVANCE: Stress kinase p38 is an important signaling pathway in stress-response. Our proposal will investigate the molecular mechanisms and functional role of a novel non-canonical activation pathway of p38 and its impact on crosstalk from myocyte to endothelial cells. These studies will improve our current understanding to the disease mechanisms of heart failure and provide potential insights for development of better treatment.