TIM Family of Genes: Role in T Cell Immunity and Tolerance

TIM 基因家族：在 T 细胞免疫和耐受中的作用

• 批准号: 8298452
• 负责人: VIJAY K. KUCHROO
• 金额: $ 166.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-22 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298452
• 关键词: Address; Animal Model; Antibodies; Antigen-Presenting Cells; Asthma; Autoimmune Process; Autoimmunity; Chimeric Proteins; Data; Disease; Family; Gene Family; Graft Rejection; Grant; Human; Immune; Immune response; Immune system; Immunity; Immunoglobulins; Inflammatory; Knock-out; Mediating; Mucins; Pathway interactions; Peripheral; Play; Proteins; Reagent; Regulation; Research Personnel; Research Project Grants; Role; Signal Pathway; T cell response; T-Cell Activation; T-Lymphocyte; Therapeutic; Tissues; Transgenic Organisms; Transplantation Tolerance; Tumor Immunity; base; cost effective; human disease; mouse model; research study; tool

DESCRIPTION (provided by applicant): In this revised PPG, we propose to analyze the function of a new family of genes that we have recently discovered called TIM (T cell Immunoglobulin and Mucin domain containing molecules), which was initially shown to be expressed in T cells and play a crucial role in regulating immunity and tolerance. However, recent data suggests that TIM molecules are not only expressed on T cells but also expressed on antigen presenting cells (APC) in the peripheral immune compartment and in target tissues. The role of TIM molecules in regulating the function of T cells vs. APCs is not well understood. Preliminary data suggest that the TIM family of molecules can positively or negatively costimulate T cell activation and also promote APC activation. Based on these observations, we hypothesize that this family of molecules may have a very important role in regulating both innate and adaptive immune systems and could be exploited in a number of diseases and inflammatory conditions, including autoimmunity, asthma, transplant rejection and tumor immunity. This PPG brings together 3 research projects and 3 cores, involving 11 independent investigators, to address the role of the TIM family of molecules in autoimmunity and transplant rejection. The proposed studies will utilize and examine animal models and human disease conditions. The three projects are highly interdependent and address a common theme: What is the role of the TIM family of molecules in regulating immunity and tolerance? The main themes of the three projects are: 1. The roles of the TIM family of genes in regulating autoimmune T cell responses in mouse models (Project I: Vijay Kuchroo and Joan Goverman, PIs); 2. TIM- 3 regulation of immune responses in the CNS in humans (Project II: David Hafler, David Anderson and Larry Kane PIs); 3. TIM proteins in regulation of transplantation tolerance (Project III: Terry Strom, Wenda Gao and Larry Kane PI). To understand the mechanism by which TIM protein mediate their function in adaptive and innate immune system, in the revised grant we have included a new co-PI (Larry Kane) on projects 2 and 3 to analyze the signaling pathways induced by TIM molecules. The three cores (Administrative, Antibody/lg- fusion protein, Transgenic/Knock-out core) will support these three projects and provide tools that will be shared by all the projects, thus accelerating discovery in an efficient and cost effective manner. Lay Summary: By sharing a set of common set of standardized reagents and information, and conducting complementary experiments in animal models and humans and among different types of inflammatory diseases, the PPG will build a comprehensive understanding of the role of the TIM family of genes in regulation of immunity and tolerance with the potential of exploiting this pathway for therapeutic purposes in humans.

描述（由申请人提供）：在此修订后的PPG中，我们建议分析我们最近发现的一种新的基因家族的功能，该基因家族的功能称为Tim（T细胞免疫球蛋白和含有分子的粘蛋白结构域），最初被证明在T细胞中表达并在调节免疫和耐受性中起着至关重要的作用。但是，最近的数据表明，蒂姆分子不仅在T细胞上表达，而且在外围免疫区室和靶组织中的抗原呈递细胞（APC）表达。蒂姆分子在调节T细胞与APC的功能中的作用尚不清楚。初步数据表明，TIM分子家族可以积极或负面刺激的T细胞激活并促进APC激活。基于这些观察结果，我们假设该分子家族在调节先天和适应性免疫系统方面可能具有非常重要的作用，并且可以在多种疾病和炎症状况中被剥削，包括自身免疫，哮喘，哮喘，移植排斥和肿瘤免疫。该PPG汇集了3个研究项目和3个核心，涉及11位独立研究人员，以解决Tim分子家族在自身免疫和移植排斥中的作用。拟议的研究将利用和检查动物模型和人类疾病状况。这三个项目是高度相互依存的，并且要解决一个共同的主题：蒂姆分子家族在调节免疫和宽容中的作用是什么？这三个项目的主要主题是：1。蒂姆基因家族在调节鼠标模型中自身免疫T细胞反应中的作用（项目I：Vijay Kuchroo和PIS）； 2。蒂姆 - 3在人类中枢神经系统中对免疫反应的调节（项目II：David Hafler，David Anderson和Larry Kane Pis）； 3。调节移植耐受性的TIM蛋白（项目III：Terry Strom，Wenda Gao和Larry Kane Pi）。为了了解Tim蛋白在适应性和先天免疫系统中介导其功能的机制，在修订后的赠款中，我们在项目2和3上包括了一个新的Co-Pi（Larry Kane），以分析TIM分子诱导的信号通路。这三个核心（行政，抗体/LG-融合蛋白，转基因/敲除核心）将支持这三个项目，并提供所有项目将共享的工具，从而以有效且具有成本效益的方式加速发现。摘要摘要：通过共享一组常见的标准化试剂和信息，并在动物模型和人类中以及在不同类型的炎症性疾病中进行互补实验，PPG将对Tim家族在调节免疫力和容忍方面的作用，以利用这种对这种治疗目的的途径的潜力来建立一个全面的理解。