The small G protein Rap 1 in Tau cell activation/anergy

Tau 细胞激活/无反应中的小 G 蛋白 Rap 1

• 批准号: 6327005
• 负责人: PHILIP J.S. STORK
• 金额: $ 30.2万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6327005
• 关键词: CD28 molecule; CD3 molecule; T cell receptor; T lymphocyte; anergy; genetically modified animals; guanine nucleotide binding protein; guanosinetriphosphatases; interleukin 2; laboratory mouse; leukocyte activation /transformation; mitogen activated protein kinase; protein biosynthesis; tissue /cell culture; transfection

DESCRIPTION (Provided by the Applicant): A productive T lymphocyte response to antigen requires the activation of two signaling pathways, involving signals generated by the interactions between the T-cell receptor (TCR) with antigenic peptide presented on antigen-presenting cells (APCs) and the signal mediated by the binding of the accessory receptor CD28 with its ligand B7. Although the requirement for CD28 co-stimulation has been the subject of intensive and extensive investigation, the molecular nature of this co-stimulatory signal is unknown. Some models have identified distinct kinase cascades initiated by either the ICR or CD28, while other models have focused on the convergence of TCR/CD28 signals on particular kinase cascades. One pathway which can mediate the synergistic responses that characterize CD28 co-stimulation is the MAP kinase (ERK) cascade. The activation of the MAP kinase ERK following CD28 co-stimulation is required for IL-2 production and proliferation of responding T lymphocytes. ERK activation in T lymphocytes is regulated by two antagonistic small G proteins: Ras and Rap1. Ras activation is required for ERK activation, while Rap1 antagonizes Ras signaling. Antigen recognition by T-cells in the absence of CD28 co-stimulation is characterized by impaired ERK activation and both decreased IL-2 production and diminished proliferation. This functional unresponsiveness results in the inability to respond to subsequent co-stimulatory signals and is termed clonal anergy. Rap1 is constitutively activated in certain states of I cell anergy or this unresponsiveness may account for the diminished ERK activity and decreased IL-2 production seen in anergic T-cells. In this proposal, we will test the hypothesis that Rap1 is activated by ICR ligation in normal I cells and consequently limits I cell activation through the ICR in the absence of co-stimulation. In addition, we will test the hypothesis that CD28 co-stimulation achieves increased ERK activation, IL-2 production and proliferation by blocking Rap1 activation.

描述（由申请人提供）：生产性T淋巴细胞对 抗原需要激活两个信号途径，涉及信号 由T细胞受体（TCR）与抗原之间的相互作用产生 在抗原呈递细胞（APC）上呈现的肽和由 辅助受体CD28与其配体B7的结合。虽然 CD28共同刺激的需求一直是密集的主题 广泛的研究，该共刺激信号的分子性质是 未知。一些模型已经确定了由 ICR或CD28，而其他模型则集中于 特定激酶级联反应的TCR/CD28信号。一条可以调节的途径 表征CD28共刺激的协同响应是地图 激酶（ERK）级联。 CD28之后的MAP激酶ERK的激活 IL-2产生和响应的扩散需要共刺激 T淋巴细胞。 T淋巴细胞中的ERK激活受两个拮抗作用调节 小G蛋白：RAS和RAP1。 ERK激活需要RAS激活， Rap1拮抗RAS信号传导。 T细胞在 CD28共刺激的缺乏的特征是ERK激活受损和 两者都降低了IL-2的产生，并减少了增殖。这个功能 无反应性导致无法应对随后的 联合刺激信号，称为克隆语。 Rap1是组成型 在某些I细胞消极的状态或这种不响应的状态中激活 占ERK活性降低并减少IL-2产生的原因 厌食症的T细胞。在此提案中，我们将测试Rap1是 通过正常I细胞中的ICR连接激活，因此限制了I细胞 在没有共刺激的情况下通过ICR激活。另外，我们 将测试CD28共刺激实现ERK的假设 通过阻断RAP1激活，激活，IL-2产生和增殖。