Regulatory targets of p38 MAP kinase in inflammation

描述(申请人提供)：三个不同的MAPK通路，每一个都由细胞外信号调节蛋白激酶(ERK)、c-Jun氨基末端激酶(JNK)和p38MAPK介导，调节细胞对各种细胞外刺激的反应。在物理应激、组织损伤和感染等条件下，这些MAPK信号级联信号通路通过直接的、细胞自主的方式或通过细胞间细胞因子信号被激活，并负责调节细胞的生存和适应。在我们长期探索MAPKs在炎症性疾病发病机制中的作用的过程中，我们特别关注p38信号通路。在哺乳动物中p38MAPK的四种亚型中，p38？是目前表达最广泛的蛋白，似乎介导了对目前可用的p38抑制剂敏感的大部分p38 MAPK作用。靶向缺失p38？小鼠的基因会导致早期胚胎死亡，从而使成人组织中p38功能的检测复杂化。在这个项目中，我们的目标是评估p38？在炎症反应中的信号转导并确定p38？调节炎症基因的表达。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？2)确定p38的调控靶点。并确定它们的炎症功能；3)阐明p38？向靶基因表达发出信号。这里提出的实验结果将使我们能够更好地理解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：我们的目标是通过研究细胞内传递炎症信号的分子，了解伤害性刺激如何引发炎症反应。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.