The role of SLP-76 phosphorylation in T cell development

SLP-76 磷酸化在 T 细胞发育中的作用

• 批准号: 7660322
• 负责人: MARTHA S JORDAN
• 金额: $ 12.76万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660322
• 关键词: Actins; Address; Affect; Arthritis; Autoimmune Diseases; Binding; Biochemical; Breeding; C-terminal; Cell Line; Cell physiology; Cellular Immunology; Complement; Defect; Disease; Ensure; Event; Faculty; Genes; In Vitro; Individual; Institutes; Jordan; Jurkat Cells; Knock-in Mouse; LCP2 gene; Lead; MHC Class I Genes; MHC Class II Genes; Mature T-Lymphocyte; Methods; Molecular Immunology; Mus; Mutate; Mutation; N-terminal; Partner in relationship; Pennsylvania; Peripheral; Phosphorylation; Play; Process; Proline-Rich Domain; Protein Binding; Proteins; Proteomics; Reagent; Research; Research Personnel; Role; Services; Signal Transduction; T cell differentiation; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Tamoxifen; Technology; Testing; Thymocyte Development; Thymocyte Selection; Training; Transgenic Mice; Tyrosine; Tyrosine Phosphorylation Site; Universities; Work; in vivo; mutant; reconstitution; src Homology Region 2 Domain; success; thymocyte; tool

DESCRIPTION (provided by applicant): Engagement of the T cell receptor (TCR) triggers a number of intracellular signaling events that lead to the differentiation and activation of T cells. Several studies have shown that SLP-76 plays a central role in T cell activation and T cell development, as mice deficient in SLP-76 lack mature T cells. SLP-76 has three functional domains: an acidic domain with three phosphorylatable tyrosines, a central proline-rich domain, and a C-terminal SH2 domain. Of these domains, mutation of the three N-terminal tyrosines results in the most profound defects in T cell development and function. It is hypothesized that the individual tyrosines of SLP-76 activate specific signaling cascades required for T cell development including thymocyte selection, and T cell differentiation and function. This hypothesis will be tested by 1) analyzing SLP-76 deficient Jurkat cells reconstituted with SLP-76 bearing mutations at one or multiple tyrosine phosphorylation sites, 2) analyzing SLP-76 knock-in mice expressing tyrosine mutations at particular tyrosine residues and 3) mating SLP-76 knock-in mice to T cell receptor transgenic mice to evaluate thymocyte selection and mechanisms of T cell tolerance. Understanding how T cells transmit signals to direct thymocyte development and mature T cell function is critical to understanding the mechanisms to drive several disease processes including autoimmune diseases such as arthritis. This work will be performed by Dr. Martha S. Jordan at the Abramson Institute at the University of Pennsylvania. Dr. Jordan's background in cellular immunology and current training in molecular immunology provides her with a distinct angle from which to approach questions of T cell development. This proposal will provide her with the tools and reagents required to study T cell function in vitro and in vivo, in normal and diseased states as an independent investigator at a research university. Full access to faculty and services provided by the University of Pennsylvania, especially those within the Abramson Institute, will ensure the success of this proposal.

描述（由申请人提供）：T细胞受体（TCR）的参与触发许多导致T细胞分化和激活的细胞内信号事件。几项研究表明，SLP-76在T细胞激活和T细胞发育中起着核心作用，因为缺乏SLP-76的小鼠缺乏成熟的T细胞。 SLP-76具有三个功能域：具有三个可磷酸磷酸酪氨酸的酸性结构域，一个富含脯氨酸的中央域和一个C末端SH2结构域。在这些域中，三种N末端酪氨酸的突变导致T细胞发育和功能中最深刻的缺陷。假设SLP-76的各个酪氨酸激活T细胞发育所需的特定信号级联，包括胸腺细胞选择，T细胞分化和功能。 This hypothesis will be tested by 1) analyzing SLP-76 deficient Jurkat cells reconstituted with SLP-76 bearing mutations at one or multiple tyrosine phosphorylation sites, 2) analyzing SLP-76 knock-in mice expressing tyrosine mutations at particular tyrosine residues and 3) mating SLP-76 knock-in mice to T cell receptor transgenic mice to evaluate thymocyte selection and T细胞耐受的机理。了解T细胞如何将信号传输到指导胸腺细胞发育和成熟的T细胞功能对于理解驱动包括自身免疫性疾病（如关节炎）的多种疾病过程的机制至关重要。这项工作将由宾夕法尼亚大学艾布拉姆森学院的玛莎·乔丹（Martha S. Jordan）博士进行。约旦博士在细胞免疫学方面的背景和分子免疫学的当前培训为她提供了一个独特的角度，可以解决T细胞发育的问题。该提案将为她提供体外和体内研究T细胞功能所需的工具和试剂，在正常和患病的状态下，作为研究大学的独立研究者。宾夕法尼亚大学提供的教职员工和服务，尤其是艾布兰森学院内的教师和服务，将确保该提议的成功。