RAS PROTEINS IN T CELL ACTIVATION AND DIFFERENTIATION

T 细胞激活和分化中的 RAS 蛋白

• 批准号: 6372712
• 负责人: Jan Czyzyk
• 金额: $ 11.59万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6372712
• 关键词: T cell receptor; T lymphocyte; biological signal transduction; cell differentiation; genetically modified animals; guanine nucleotide binding protein; laboratory mouse; leukocyte activation /transformation; training

DESCRIPTION (adapted from application abstract): The long term objective of the proposed research is to characterize how the potency of the T cell receptor (TCR) signals affects the activity of the Ras family of small GTPases. 'I'CR signals will be viewed by altering the contribution of the CD45 protein tyrosine phosphatase and by using ligands of varying affinities for the TCR. Thee studies will explore the hypothesis that small GTPases Ras and related protein Rapl do not act in isolation from each other but rather remain in close functional relationships which may effectively integrate and modify signal transduction events induced by the TCR complex. The applicant hypothesizes that depending on the isoform of CD 45 and the strength of the T cell receptor ligation, either antagonistic or synergistic arrangements between Ras and Rap1 are included, and that these different relationships which may influence lymphocyte behaviors such as T cell early development, differentiation of matured cells into Th1 or 'I'h2 helper subsets, and the generation of memory T cell pools. In aim 1, the biochemical and functional experiments will examine the effect s of single CD45 isoforms on Ras and Rapl with respect to their immediate downstream targets and the direct upstream stimulators, the Raf kinases and the guanine nucleotide exchange factors (GEFs) respectively. Because individual.. CD4: isoforms are believed to differentially modify responsiveness of T cells to TCR induction information obtained in these studies will model approaches in aim 2 in which the effects of TCR stimulation with high affinity wild type peptide or low affinity altered peptide ligand, will be analyzed. In particular, following, these stimulations, the applicant will evaluate biochemical activities of Ras and Rapl, and examine functional properties of RAP1 to enhance or suppress Ras- signaling effects on mitogen activated protein kinase (MPK). The applicant plans to eventually deliver the dominant negative or constitutive active mutants of Ras or Rap1 into primary T cells and to test their potential to interfere with the functional polarization processes occurring during immune response. Understanding the molecular mechanisms controlling the activation and differentiation of naive T helper cells is crucial with regard to a variety of immunological conditions including allergic, infectious and autoimmune diseases. In addition, basic studies on the regulation of T lymphocytes by small GTPases have broad applicability to the field of cancer pathogenesis.

描述（根据应用程序摘要改编）： 拟议的研究是表征T细胞的效力 受体（TCR）信号会影响小的RAS家族的活性 GTPases。 '我将通过更改CD45的贡献来查看我的信号 蛋白质酪氨酸磷酸酶，并通过使用不同亲和力的配体进行 TCR。您的研究将探讨一个假说，即小gtpases ras和 相关蛋白质Rapl不会彼此孤立起作用，而是保持 在密切的功能关系中，可以有效整合和修改 TCR复合物诱导的信号转导事件。 申请人 假设根据CD 45的同工型和T的强度 细胞受体连接，无论是拮抗还是协同布置 包括Ras和Rap1之间，并且这些不同的关系 可能影响淋巴细胞行为，例如T细胞早期发育， 分化成熟的细胞为th1或'i'h2辅助子集，然后 记忆T细胞池的生成。 在AIM 1中，生化和功能 实验将检查单个CD45同工型对RA和RAPL的效果 关于它们的直接下游目标和上游的直接目标 刺激剂，RAF激酶和鸟嘌呤核苷酸交换因子 （GEFS）分别。因为个人.. CD4：同工型被认为 差异改变T细胞对TCR诱导信息的响应能力 在这些研究中获得的将模拟AIM 2的方法，其中影响 具有高亲和力野生型肽或低亲和力的TCR刺激 将分析肽配体的改变。特别是，这些 刺激，申请人将评估RAS的生化活动 RAPL，并检查RAP1的功能特性以增强或抑制Ras- 信号传导对有丝分裂激活的蛋白激酶（MPK）的作用。 申请人 计划最终提供主要的负面或本构主动 RAS或RAP1的突变体进入原代T细胞，并测试其潜力 干扰免疫期间发生的功能极化过程 回复。了解控制激活的分子机制 对于A的幼稚T辅助细胞的分化至关重要 各种免疫条件，包括过敏，传染性和 自身免疫性疾病。 此外，关于调节的基础研究 小型GTPases的淋巴细胞对癌症领域具有广泛的适用性 发病。