Regulatory targets of p38 MAP kinase in inflammation

p38 MAP 激酶在炎症中的调节靶点

• 批准号: 7804560
• 负责人: Jin Mo Park
• 金额: $ 38.43万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/7804560
• 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; Figs - dietary; 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

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.

描述（由申请人提供）：三种不同的MAP激酶（MAPK）途径，分别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。在生理应激、组织损伤和感染条件下，这些MAPK信号级联要么以直接的、细胞自主的方式激活，要么通过细胞间细胞因子信号传导激活，并负责调节细胞的生存和适应。在我们对炎性疾病发病机制中MAPKs功能的长期探索中，我们特别关注了p38信号通路。在哺乳动物p38 MAPK的四种同工异构体中，p38？是最广泛表达的蛋白，并且似乎介导大多数（如果不是全部的话）对目前可用的p38抑制剂敏感的p38 MAPK作用。靶向删除p38？基因在小鼠中导致早期胚胎致死，从而使p38在成年组织中功能的检测复杂化。在这个项目中，我们的目标是评估p38？炎症反应中的信号并确定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？在小鼠炎症模型中；2)确定p38？骨髓、淋巴和上皮组织并测定其炎症功能；3)阐明p38？向目标基因表达的信号。本文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。公共卫生相关性：我们旨在通过研究细胞中传递炎症信号的分子来了解有害刺激如何诱导炎症反应。我们的研究将为炎症性疾病的治疗提供新的见解。