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

描述（由申请人提供）：对以下的生产性T淋巴细胞应答： 抗原需要激活两个信号通路，包括信号 由T细胞受体（TCR）与抗原性 抗原呈递细胞（APC）上呈递的肽和由 辅助受体CD 28与其配体B7的结合。虽然 对CD 28共刺激的需求一直是密集和 广泛的研究表明，这种共刺激信号的分子本质是 未知一些模型已经确定了由以下启动的不同的激酶级联： 无论是ICR还是CD 28，而其他模型都专注于融合 TCR/CD 28信号在特定的激酶级联。一种途径可以介导 表征CD 28共刺激的协同反应是MAP 激酶（ERK）级联。CD 28介导的MAP激酶ERK的活化 IL-2的产生和应答细胞的增殖需要共刺激。 T淋巴细胞。T淋巴细胞中ERK的激活受两种拮抗剂的调节 小G蛋白：Ras和Rap 1。Ras激活是ERK激活所必需的， 而Rap 1拮抗Ras信号。T细胞对抗原的识别 缺乏CD 28共刺激的特征在于ERK活化受损， 都降低了IL-2的产生并减少了增殖。该功能 反应迟钝导致无法对随后的 共刺激信号，称为克隆无反应性。Rap 1是一种 在I细胞无反应性的某些状态下被激活，或者这种无反应性可能 解释了ERK活性降低和IL-2产生减少， 无反应性T细胞在这个提议中，我们将测试Rap 1是 在正常I细胞中通过ICR连接激活，从而限制I细胞 在不存在共刺激的情况下通过ICR激活。另外我们 将测试CD 28共刺激实现ERK增加的假设 通过阻断Rap 1活化，IL-2产生和增殖。

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.