Regulatory targets of p38 MAP kinase in inflammation

描述（由申请人提供）：三种不同的MAP激酶（MAPK）途径，每种途径由细胞外信号调节蛋白激酶（ERK）、c-Jun N-末端激酶（JNK）和p38 MAPK介导，调节细胞对各种细胞外刺激的反应。在物理应激、组织损伤和感染的条件下，这些MAPK信号传导级联以直接的、细胞自主的方式或通过细胞间细胞因子信号传导被激活，并且负责调节细胞存活和适应。在我们长期探索了解MAPKs在炎症性疾病发病机制中的功能时，我们特别关注p38信号通路。在哺乳动物中p38 MAPK的四种亚型中，p38？是最广泛表达的蛋白质，并且似乎介导对目前可用的p38抑制剂敏感的大多数（如果不是全部的话）p38 MAPK作用。p38基因的靶向缺失？小鼠中的p38基因导致早期胚胎死亡，从而使成年组织中p38功能的检查复杂化。在这个项目中，我们的目标是评估细胞类型的特定要求的p38？信号在炎症反应，并确定机制，p38？调节炎症基因表达。为此，我们计划追求以下具体目标：1）确定p38的细胞类型特异性功能？在小鼠模型的炎症; 2）确定的调控目标的p38？在骨髓，淋巴，上皮组织，并确定其炎症功能;和3）阐明的机制，连接p38？信号传导到靶基因表达。本文提出的实验结果将使人们能够更好地理解p38 MAPK通路，并为炎症性疾病的治疗提供新的见解。公共卫生相关性：我们的目标是了解如何伤害性刺激诱导炎症反应，通过调查分子，在细胞中传递炎症信号。我们的研究将为炎症性疾病的治疗提供新的见解。

DESCRIPTION (provided by applicant): Three distinct MAP kinase (MAPK) pathways, each mediated by the extracellular signal regulated protein kinases (ERK), the c-Jun N-terminal kinases (JNK) and the p38 MAPK, regulate the response of cells to a variety of extracellular stimuli. Under conditions of physical stress, tissue injury and infection, these MAPK signaling cascades are activated either in a direct, cell-autonomous manner or via intercellular cytokine signaling, and responsible for regulating cell survival and adaptation. In our long-term quest for understanding the function of MAPKs in the pathogenesis of inflammatory diseases, we have focused specifically on the p38 signaling pathway. Of the four isoforms of p38 MAPK in mammals, p38? is the most widely expressed protein and appears to mediate most, if not all, of the p38 MAPK actions that are sensitive to currently available p38 inhibitors. Targeted deletion of the p38? gene in mice results in early embryonic lethality, thus complicating the examination of p38 function in adult tissues. In this project, we aim to assess the cell type-specific requirement of p38? signaling in inflammatory responses and determine the mechanism by which p38? regulates inflammatory gene expression. To this end, we plan to pursue the following Specific Aims:1) Determine the cell type-specific functions of p38? in mouse models of inflammation; 2) Identify the regulatory targets of p38? in myeloid, lymphoid, and epithelial tissues and determine their inflammatory function; and 3) Elucidate the mechanisms that link p38? signaling to target gene expression. Findings from the experiments proposed here will enable a better understanding of the p38 MAPK pathway and offer new insight into the treatment of inflammatory diseases. Public Health Relevance: We aim to understand how injurious stimuli induce inflammatory responses through investigation of molecules that relay inflammatory signals in the cell. Our study will offer new insight into the treatment of inflammatory diseases.