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: 7921260
• 负责人: Yibin Wang
• 金额: $ 38.5万
• 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/7921260
• 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; Hand; 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. 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.

描述（由申请人提供）： 心力衰竭是一种普遍存在的疾病，没有有效的治疗方法，在美国代表着一个未得到满足的重大医疗需求。为了应对病理应激，心脏在分子、细胞和器官水平上经历深刻的重塑。在之前的研究中，我们和其他人已经确定，压力激活蛋白激酶 p38 在介导压力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 的组成性激活会导致收缩性丧失和与促炎细胞因子诱导相关的病理重塑。然而，我们还观察到 p38 基因失活会导致慢性压力或衰老下的生存受损和功能障碍。这一悖论表明 p38 介导的信号传导在心脏的有害和保护机制中发挥着复杂的作用，这对于心力衰竭的 p38 靶向治疗的发展具有重要意义。为了更好地了解 p38 介导的心脏信号传导的潜在机制，我们在分子、细胞和功能水平上对 p38 信号传导复合物和 p38 介导的功能进行了广泛的研究。特别是，我们已经确定，自磷酸化诱导的非经典 p38 途径受到一种新型相互作用伙伴 Hsp90/Cdc37 复合物的调节。我们还发现，p38 活性通过从心肌细胞到内皮细胞的旁分泌串扰对心脏代偿性血管重塑至关重要。最后，我们证明了成熟的 p38 下游激酶 MK2 对 p38 诱导的心脏病理变化具有选择性贡献。这些新发现引出了我们目前的假设，即 p38 激活和下游靶点的不同机制有助于 p38 信号在心脏代偿和病理重塑中的特定作用。在当前的提案中，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了解：1)。确定心脏中非经典 p38 激酶激活的分子机制和功能意义。 2）。描述心脏病理重塑过程中 p38 介导的心肌细胞和内皮细胞串扰调节的机制。 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。这些研究将显着推进我们目前对心力衰竭疾病机制的了解，并有助于开发更有效的治疗方法。 公共卫生相关性： 应激激酶p38是应激反应中重要的信号通路。我们的提案将研究 p38 的新型非经典激活途径的分子机制和功能作用及其对心肌细胞到内皮细胞串扰的影响。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。