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（改编自申请摘要）：长期目标 拟议的研究旨在表征 T 细胞的效力如何 受体 (TCR) 信号影响小分子 Ras 家族的活性 GT酶。 'I'CR 信号将通过改变 CD45 的贡献来查看 蛋白酪氨酸磷酸酶并通过使用不同亲和力的配体 TCR。这些研究将探讨小 GTPases Ras 和 相关蛋白 Rapl 不会彼此孤立地发挥作用，而是保持不变 密切的功能关系可以有效地整合和修改 TCR 复合物诱导的信号转导事件。 申请人 假设取决于 CD 45 的亚型和 T 的强度 细胞受体连接，拮抗或协同排列 Ras 和 Rap1 之间的关系都包含在内，并且这些不同的关系 这可能会影响淋巴细胞的行为，例如 T 细胞的早期发育， 成熟细胞分化为 Th1 或 'I'h2 辅助亚群，以及 记忆T细胞池的产生。 在目标 1 中，生化和功能 实验将检查单个 CD45 同工型对 Ras 和 Rapl 的影响 就其直接下游目标和直接上游而言 刺激剂、Raf 激酶和鸟嘌呤核苷酸交换因子 （全球环境基金）。因为个体.. CD4：亚型被认为 差异性地改变 T 细胞对 TCR 诱导信息的反应 这些研究中获得的结果将模拟目标 2 中的方法，其中效果 高亲和力野生型肽或低亲和力的 TCR 刺激 将分析改变的肽配体。特别是，以下这些 刺激，申请人将评估Ras和的生化活性 Rapl，并检查 RAP1 的功能特性以增强或抑制 Ras- 对丝裂原激活蛋白激酶（MPK）的信号传导作用。 申请人 计划最终提供主导消极或本构积极 Ras 或 Rap1 突变体进入原代 T 细胞并测试其潜力 干扰免疫过程中发生的功能极化过程 回复。了解控制激活的分子机制 幼稚 T 辅助细胞的分化对于 各种免疫性疾病，包括过敏性、感染性和 自身免疫性疾病。 此外，T调控的基础研究 小 GTP 酶产生的淋巴细胞在癌症领域具有广泛的适用性 发病。