Regulatory targets of p38 MAP kinase in inflammation

p38 MAP 激酶在炎症中的调节靶点

基本信息

批准号：
8440849
负责人：
Jin Mo Park
金额：
$ 35.76万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-20 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8440849
关键词：
Adult Anti-Inflammatory Agents Anti-inflammatory Bacterial Infections Cell Survival Cells Chronic Clinical Contact hypersensitivity Cytokine Signaling Data Disease Embryo Enterocytes Epithelial Epithelial Cells Event Exhibits Gene Expression Gene Targeting Genes Genetic Transcription Goals Healed Immune Immune system Immunity Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Investigation Knockout Mice Knowledge Link Lymphoid MAP Kinase Modules MAPK14 gene Mammals Mediating Methods Mitogen-Activated Protein Kinases Mus Mutant Strains Mice Myelogenous Myeloid Cells Pathogenesis Pathway interactions Patients Physiological Protein Isoforms Protein Kinase Proteins Role Signal Pathway Signal Transduction Skin Stimulus Stress T-Lymphocyte Testing Therapeutic Tissues Transducers base cell type extracellular healing in vitro Assay in vivo inhibitor/antagonist insight irritation keratinocyte macrophage microbial mitogen-activated protein kinase p38 mouse model novel physical conditioning prevent programs public health relevance research study response stress-activated protein kinase 1 therapeutic target transcription factor ultraviolet

项目摘要

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.

描述（由申请人提供）：三种不同的 MAP 激酶 (MAPK) 途径，每种途径均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，调节细胞的反应来应对各种细胞外刺激。在身体应激、组织损伤和感染的情况下，这些 MAPK 信号级联以直接、细胞自主的方式或通过细胞间细胞因子信号传导被激活，并负责调节细胞存活和适应。在我们长期探索 MAPK 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。哺乳动物中 p38 MAPK 的四种亚型中，p38？是表达最广泛的蛋白质，并且似乎介导对当前可用的 p38 抑制剂敏感的大多数（如果不是全部）p38 MAPK 作用。定向删除p38？小鼠体内的 p38 基因会导致早期胚胎死亡，从而使成体组织中 p38 功能的检查变得复杂。在这个项目中，我们的目标是评估 p38 的细胞类型特异性要求？炎症反应中的信号传导并确定 p38 的机制？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？在小鼠炎症模型中； 2）确定p38的监管靶点？在骨髓、淋巴和上皮组织中进行检测并确定它们的炎症功能； 3) 阐明连接 p38 的机制？向目标基因表达发出信号。这里提出的实验结果将有助于更好地理解 p38 MAPK 通路，并为炎症性疾病的治疗提供新的见解。