MAP3K8-mediated regulation of adaptive immune responses and autoimmunity

MAP3K8 介导的适应性免疫反应和自身免疫的调节

• 批准号: 8439506
• 负责人: Wendy T Watford
• 金额: $ 13.96万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439506
• 关键词: Ablation; Address; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Autoimmune Diseases; Autoimmunity; Biological Assay; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Colitis; Communicable Diseases; Cytokine Signaling; Data; Development; Disease; Disease Management; Epidemic; Equilibrium; Gene Expression; Generations; Goals; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Immune; Immune response; Immunologics; Immunosuppressive Agents; Immunotherapy; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Insulin-Dependent Diabetes Mellitus; Interleukin-17; Intervention; Knowledge; Light; MAP Kinase Gene; MAP3K8 gene; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Multiple Sclerosis; Mus; Nuclear Translocation; Outcome; Parasites; Pathogenesis; Pathologic; Pathway interactions; Play; Population; Predisposition; Prevention; Process; Production; Protein-Serine-Threonine Kinases; Psoriasis; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Research; Rheumatoid Arthritis; Role; STAT4 gene; Self Tolerance; Severity of illness; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Specific qualifier value; T Cell Receptor Signaling Pathway; T cell therapy; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Tissues; To specify; Toxoplasma gondii; Transgenic Mice; Transplanted tissue; Western Blotting; Work; cell motility; chronic graft versus host disease; cytokine; in vivo; inhibitor/antagonist; innovation; insight; interest; mTOR protein; novel; programs; public health relevance; research study; response; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Autoimmune diseases are approaching epidemic levels, estimated to affect 5-8% of the U.S. population. Pathogenesis is attributed, in large part, to self-reactive T cells that recognize auto-antigens in affected tissues and secrete destructive, pro-inflammatory cytokines. Consequently, the differentiation of naive T cells into pro- inflammatory versus tolerogenic T helper cell lineages regulates the immunologic state of the host. T cell receptor (TCR) signals, along with local cytokines, are required for initiating T helpr cell differentiation. Understanding the precise molecular mechanisms contributing to TCR signal integration and T helper cell differentiation is important when considering immunotherapies for T cell-mediated diseases, particularly autoimmunity. We recently demonstrated that Map3k8 transduces TCR signals in naive T cells and helps to specify a Th1 transcriptional program. What is not clear is precisely how Map3k8 impinges upon the multiple TCR signaling pathways to regulate the development and functions of other T helper cell lineages. The goal of this proposal is to determine how the serine-threonine kinase Map3k8 influences TCR signaling, T helper cell differentiation, and autoimmunity. Our central hypothesis is that Map3k8 modulates TCR signal integration and thereby alters lineage commitment and effector functions of T cells in vivo. Aim1 seeks to determine which TCR signaling pathways are defective in Map3k8-/- T cells using gene expression assays, Western blotting, and transcription factor nuclear translocation. Aim2 will examine how Map3k8 influences T helper cell differentiation and will address the roles of specific signaling molecules and pathways in specifying T helper cell fates using in vitro T cell polarization assays and analysis of T cell populations in mice with Map3k8 ablation. Aim3 will determine how Map3k8 contributes to T cell-mediated autoimmunity using genetically altered animal models and Map3k8 pharmacologic inhibitors. Experiments will address the underlying mechanisms of disease (or protection) by analyzing T cell migration, accumulation, and effector functions of Map3k8-/- T cells. Knowledge gained about the role of Map3k8 in TCR signaling networks will not only contribute to our fundamental understanding of normal T cell development and functions, but will also provide insight into the pathogenesis of autoimmune diseases that may ultimately elicit innovative approaches to their treatment and prevention.

描述（由申请人提供）：自身免疫性疾病正在接近流行水平，估计影响5-8%的美国人口。发病机制在很大程度上， 自身反应性T细胞识别受影响组织中的自身抗原并分泌破坏性促炎细胞因子。因此，初始T细胞分化成促炎性与致耐受性T辅助细胞谱系调节宿主的免疫状态。T细胞受体（TCR）信号沿着局部细胞因子是启动辅助T细胞分化所必需的。理解有助于TCR信号整合和T辅助细胞分化的精确分子机制在考虑T细胞介导的疾病，特别是自身免疫的免疫疗法时是重要的。我们最近证明了Map 3 k8在幼稚T细胞中转导TCR信号，并有助于指定Th 1转录程序。目前尚不清楚Map 3 k8是如何影响多种TCR信号通路来调节其他T辅助细胞谱系的发育和功能的。该提案的目标是确定丝氨酸-苏氨酸激酶Map 3 k8如何影响TCR信号传导、T辅助细胞分化和自身免疫。我们的中心假设是Map 3 k8调节TCR信号整合，从而改变体内T细胞的谱系定型和效应子功能。Aim 1试图使用基因表达测定、蛋白质印迹和转录因子核转位来确定哪些TCR信号通路在Map 3 k8-/- T细胞中是有缺陷的。Aim 2将研究Map 3 k8如何影响T辅助细胞分化，并将使用体外T细胞极化试验和Map 3 k8消融小鼠T细胞群分析来解决特定信号分子和途径在指定T辅助细胞命运中的作用。Aim 3将使用遗传改变的动物模型和Map 3 k8药理学抑制剂来确定Map 3 k8如何促进T细胞介导的自身免疫。实验将通过分析T细胞迁移，积累和Map 3 k8-/- T细胞的效应功能来解决疾病（或保护）的潜在机制。关于Map 3 k8在TCR信号网络中的作用的知识不仅有助于我们对正常T细胞发育和功能的基本理解，而且还将提供对自身免疫性疾病发病机制的深入了解，最终可能引发治疗和预防的创新方法。