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

基本信息

批准号：
9181374
负责人：
Wendy T Watford
金额：
$ 37.13万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9181374
关键词：
Ablation Address Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Autoantigens Autoimmune Diseases Autoimmunity Biological Assay CD4 Positive T Lymphocytes Cell Differentiation process Cell Lineage Colitis Communicable Diseases Cytokine Signaling Data Development Disease Disease Management Effector Cell Epidemic Equilibrium FRAP1 gene Gene Expression Profiling Generations Genetic Transcription Goals Health Helper-Inducer T-Lymphocyte Homeostasis Human Immune Immune response Immunologics Immunosuppressive Agents Immunotherapy Impairment In Vitro Infection Inflammation Inflammatory Inflammatory Bowel Diseases Insulin-Dependent Diabetes Mellitus Interferons 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 Pharmacology Play Population Predisposition Prevention Process Production Protein-Serine-Threonine Kinases Psoriasis Receptor Signaling Regulation Regulatory T-Lymphocyte Research Rheumatoid Arthritis Role STAT4 protein 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 adaptive immune response cell motility chronic graft versus host disease cytokine experimental study in vivo inhibitor/antagonist innovation insight interest mouse model novel novel therapeutics polarized cell programs public health relevance response targeted treatment therapeutic candidate transcription factor

项目摘要

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）：自身免疫性疾病已接近流行病水平，估计影响 5-8% 的美国人口。发病机制在很大程度上归因于，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，幼稚 T 细胞分化为促炎性 T 辅助细胞谱系与耐受性 T 辅助细胞谱系可调节宿主的免疫状态。 T 细胞受体 (TCR) 信号以及局部细胞因子是启动 T 辅助细胞分化所必需的。在考虑 T 细胞介导的疾病（尤其是自身免疫性疾病）的免疫治疗时，了解 TCR 信号整合和 T 辅助细胞分化的精确分子机制非常重要。我们最近证明，Map3k8 在初始 T 细胞中转导 TCR 信号，并有助于指定 Th1 转录程序。目前尚不清楚 Map3k8 究竟如何影响多个 TCR 信号通路来调节其他 T 辅助细胞谱系的发育和功能。该提案的目标是确定丝氨酸-苏氨酸激酶 Map3k8 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 Map3k8 调节 TCR 信号整合，从而改变体内 T 细胞的谱系定型和效应功能。 Aim1 试图利用基因表达测定、蛋白质印迹和转录因子核转位来确定 Map3k8-/- T 细胞中哪些 TCR 信号通路存在缺陷。 Aim2 将研究 Map3k8 如何影响 T 辅助细胞分化，并将利用体外 T 细胞极化测定和对 Map3k8 消融小鼠中 T 细胞群的分析来解决特定信号分子和通路在指定 T 辅助细胞命运中的作用。 Aim3 将使用基因改造的动物模型和 Map3k8 药物抑制剂来确定 Map3k8 如何促进 T 细胞介导的自身免疫。实验将通过分析 Map3k8-/- T 细胞的 T 细胞迁移、积累和效应器功能来解决疾病（或保护）的潜在机制。了解 Map3k8 在 TCR 信号网络中的作用不仅有助于我们对正常 T 细胞发育和功能的基本了解，还将深入了解自身免疫性疾病的发病机制，最终可能引发治疗和预防的创新方法。