Novel Function and Regulatory Mechanisms of Stress Kinase p38 in Heart

心脏应激激酶p38的新功能和调节机制

• 批准号: 8442307
• 负责人: Yibin Wang
• 金额: $ 36.29万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-02 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442307
• 关键词: Address; Affect; Age; Animals; Biological Preservation; Biology; Cardiac; Cardiac Myocytes; Cell Death; Cell Proliferation Regulation; Chronic Disease; Chronic stress; Complex; Development; Disease; Drops; Endothelial Cells; Endothelium; Eukaryota; Extracellular Matrix; Family; Functional disorder; Gene Expression; Gene Expression Regulation; Genetic; Genetic Models; Growth; Heart; Heart failure; Hypertrophy; Inflammatory; Inflammatory Response; Investigation; Knowledge; Lead; Literature; MAP3K7IP1 gene; MAPK14 gene; MUK protein kinase; Mediating; Medical; Mitogen-Activated Protein Kinases; Molecular; Muscle Cells; Organ; Pathogenesis; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Process; Production; Regulation; Reperfusion Injury; Reporting; Role; Signal Pathway; Signal Transduction; Staging; Stress; System; Testing; Vascular remodeling; Virus Diseases; Work; base; biological adaptation to stress; conditioning; cytokine; effective therapy; extracellular; fetal; hemodynamics; improved; in vivo; insight; novel; paracrine; pressure; prevent; public health relevance; response; stress activated protein kinase; stressor; therapeutic target; tool; upstream kinase

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.

描述（由申请人提供）： 心力衰竭是一种没有有效治疗的流行病，在美国是一种严重未满足的医疗需求。为了应对病理性应激，心脏在分子、细胞和器官水平上发生深刻的重塑。在以前的研究中，我们和其他人已经确定，应激激活的蛋白激酶，p38在介导应激心脏的病理变化中起着重要作用。我们已经证明，心脏中p38的组成性激活导致与促炎细胞因子诱导相关的收缩性丧失和病理性重塑。然而，我们也观察到，p38基因失活导致慢性应激或衰老下的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的复杂作用，这对心力衰竭的p38靶向治疗的发展具有重要意义。为了更好地了解p38介导的心脏信号转导机制，我们在分子、细胞和功能水平上对p38信号复合物和p38介导的心脏功能进行了广泛的研究。特别是，我们已经建立了自磷酸化诱导的非经典p38途径是由一种新的相互作用的合作伙伴，热休克蛋白90/Cdc 37复合物。我们还发现，p38活性是心脏代偿性血管重塑的关键，通过旁分泌串扰从心肌细胞到内皮细胞。最后，我们已经证明，一个完善的p38下游激酶MK2有一个选择性的贡献p38诱导的心脏病理变化。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推进我们目前对p38介导的应激信号传导的认识：1）。探讨心脏非经典p38激酶激活的分子机制及其功能意义。2）。探讨p38介导的心脏病理性重构过程中心肌细胞和内皮细胞相互作用的机制。3）。揭示p38介导的心脏应激反应中下游激酶MK2的功能意义。这些研究将大大推进我们目前对心力衰竭疾病机制的认识，并有助于开发更有效的治疗方法。