Role of SHP-1 in T cell activation and development

SHP-1 在 T 细胞激活和发育中的作用

• 批准号: 7637435
• 负责人: Ulrike Lorenz
• 金额: $ 41.19万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637435
• 关键词: Address; Affect; Alleles; Antigens; Autoimmune Process; Automobile Driving; B-Lymphocytes; Biochemical; Biological; Biological Assay; Birth; Cell Lineage; Cells; Cessation of life; Complement; Data; Development; Differentiation and Growth; Disease; Dominant-Negative Mutation; Event; Generations; Genes; Goals; Growth Factor; Hematopoietic; In Vitro; Link; Mediating; Membrane Microdomains; Molecular; Mus; Mutation; Ovarian Diseases; PTPN6 gene; Peripheral; Phenotype; Play; Population; Process; Protein Tyrosine Phosphatase; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Spleen; Suppressor-Effector T-Lymphocytes; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Thymus Gland; Tissues; Transgenes; Transgenic Organisms; base; cytokine; in vitro Assay; in vivo; in vivo Model; macrophage; mutant; protein complex; research study; thymocyte; tool

DESCRIPTION (provided by applicant): SHP-1 is a protein tyrosine phosphatase expressed predominantly in hematopoietic cells where it has been linked to negative regulation of signaling events induced by cytokines, growth factors and antigens. Mutations in the SHP-1 gene in mice cause the motheaten (me/me) phenotype. Mice homozygous for the me allele, which results in the absence of any detectable SHP-1 protein, display a variety of disorders in all hematopoietic lineages resulting in death about two to three weeks after birth. These mice provide a valuable tool to combine in vitro biochemical assays with in vivo and ex vivo biological studies. Our long term goal is to understand how SHP-1 influences the growth and differentiation of hematopoietic cells. This proposal will attempt to elucidate the involvement of SHP-1 in immature, mature and regulatory T cell development and function using a combination of biological and biochemical approaches. We have shown that a subpopulation of SHP-1 localizes to lipid rafts and that this localization is functionally relevant for TCR signaling. However, the mode of targeting SHP-1 is not known. The goal of Aim 1 is to determine the molecular mechanism driving lipid rafts localization of SHP-1 and the functional implications of lipid rafts localization: Our preliminary studies suggest that mice deficient in SHP-1 show increased numbers of CD4+CD25+ regulatory T cells in the thymus and spleen. In Aim 2, we propose to test the hypothesis that SHP-1 affects the function of CD4+CD25+ Treg cells. We will examine the strength and duration of the suppressive potential of SHP-1-deficient Treg cells using in vitro and in vivo assays, the role of SHP-1 in intracellular signaling of Treg cells. In Aim 3, we will test the T cell intrinsic requirement for SHP-1, and the role of other hematopoietic lineages deficient in SHP-1 activity on the generation/expansion of a regulatory T cell population. We will use mice carrying transgenes for inducible and tissue-specific expression of dominant negative SHP-1 mutants to address these questions. Taken together, the studies proposed here should give us a better understanding of the SHP-1 and TCR signaling. In addition, we expect to gain a better understanding of factors that influence the development and function of CD4+CD25+ Treg cells with a focus on the role of SHP-1 during these processes.

描述（由申请人提供）：SHP-1是一种蛋白质酪氨酸磷酸酶，主要在造血细胞中表达，其中它与细胞因子，生长因子和抗原引起的信号事件的负调节有关。小鼠SHP-1基因的突变导致motheaten（ME/ME）表型。 ME等位基因纯合的小鼠在没有任何可检测的SHP-1蛋白的情况下，在所有造血谱系中均表现出多种疾病，导致死亡大约两到三周后死亡。这些小鼠提供了一种有价值的工具，可以将体外生化测定与体内和体内生物学研究相结合。我们的长期目标是了解SHP-1如何影响造血细胞的生长和分化。该建议将尝试通过生物学和生化方法的组合阐明SHP-1在未成熟，成熟和调节性T细胞发育和功能中的参与。我们已经表明，SHP-1的亚群定位于脂质筏，并且该定位在功能上与TCR信号传导相关。但是，靶向SHP-1的模式尚不清楚。 AIM 1的目的是确定驱动脂质筏的分子机制的SHP-1定位以及脂质筏定位​​的功能意义：我们的初步研究表明，缺乏SHP-1的小鼠在胸腺和Spleen中的CD4+ CD25+调节性T细胞数量增加。在AIM 2中，我们建议测试SHP-1影响CD4+ CD25+ Treg细胞功能的假设。我们将使用体外和体内测定，SHP-1在Treg细胞的细胞内信号传导中的作用，研究SHP-1缺陷treg细胞的抑制潜力的强度和持续时间。在AIM 3中，我们将测试T细胞对SHP-1的内在需求，以及其他造血谱系在SHP-1活性中缺乏SHP-1活性中的作用在调节性T细胞群体的产生/扩展中的作用。我们将使用携带转基因的小鼠来诱导和组织特异性的负阴性SHP-1突变体来解决这些问题。综上所述，这里提出的研究应该使我们更好地了解SHP-1和TCR信号。此外，我们希望更好地了解影响CD4+ CD25+ Treg细胞的发展和功能的因素，重点是SHP-1在这些过程中的作用。