Regulation of the MAP kinase pathway in the CD4+ T cells

描述(由申请人提供)： 以往的研究表明，TCR刺激可显著激活Th1细胞中的p38和JNK蛋白激酶通路，但不能激活Th2细胞中的p38和JNK通路。这些数据表明，在辅助性T细胞中，p38/JNK映射激酶通路受细胞环境的调节。初步数据显示，GADD45Gamma和GADD45beta在Th1细胞中高表达，而在Th2细胞中高表达。由于GADD45家族蛋白在COS-7细胞中过表达时可以激活JNK和p38，他们推测这些分子是Th1细胞中p38和JNK活性升高的原因，并且可能对Th1细胞的功能至关重要。与假设一致的是，在Th1细胞中，GADD45Gamma的缺失显著提高了TCR刺激的p38和JNKs激活的阈值。此外，GADD45Gamma还介导Th1功能，如产生干扰素-γ和迟发性超敏反应。除了它们在Th1细胞功能中的作用外，他们还发现GADD45β是由滑膜细胞中的肿瘤坏死因子-α诱导的。因此，他们推测GADD45家族分子可能通过炎性细胞因子调节滑膜细胞中p38/JNK蛋白激酶通路的激活。由于p38/JNK蛋白通路参与了类风湿性关节炎的发病过程，他们推测GADD45家族蛋白参与了类风湿性关节炎的发生发展。为了进一步研究GADD45通路在介导p38/JNK丝裂原活化中的作用及其与类风湿性关节炎的相关性，他们提出： 目的1.用遗传学和生物信息学方法研究GADD45通路在介导TCR刺激中的作用。 目的2.研究GADD45蛋白在细胞因子激活p38/JNK信号通路中的作用。 目的：研究GADD45Gamma、GADD45beta、MEKK4基因突变在小鼠胶原性关节炎中的作用。

DESCRIPTION (provided by applicant): Previous studies have demonstrated that the p38 and JNK MAP kinase pathways are prominently activated by TCR stimulation in Th1 cells but not in Th2 cells. These data suggest that the p38/JNK MAP kinase pathways are regulated in helper T cells depending on the cell context. Preliminary data show that GADD45gamma and GADD45beta are highly expressed in Thl cells versus Th2 cells. Since GADD45 family proteins were shown to activate both JNK and p38 when over-expressed in COS-7 cells, they hypothesize that these molecules are responsible for the elevated p38 and JNK activities in Th1 cells and likely critical for the function of Th1 cells. Consistent with the hypothesis, in Th1 cells, deletion of GADD45gamma significantly elevated the threshold of TCR stimulated activation of p38 and JNKs. In addition, GADD45gamma also mediates Th1 functions such as IFN-gamma production and delayed type hypersensitivity. In addition to their roles in the function of Th1 cells, they discovered that GADD45beta is induced by TNF-alpha in synoviocytes. Therefore, they hypothesize that GADD45 family molecules may regulate the activation of the p38/JNK MAP kinase pathways in synoviocytes by inflammatory cytokines. Since the p38/JNK MAP kinase pathways are involved in the pathogenesis of rheumatoid arthritis, they hypothesize that GADD45 family proteins are involved in the development of such disease. To further study the role of GADD45 pathway in mediating the activation of p38/JNK MAP kinases and its relevance to rheumatoid arthritis, they propose to: Aim 1. Study the role of GADD45 pathway in mediating TCR stimulation using genetic and bioinformatic approaches. Aim 2. Study the role of GADD45 protein in mediating the activation of the p38/JNK MAP kinase pathway by cytokines. Aim 3. Study the effect of mutation of GADD45gamma, GADD45beta, or MEKK4 in murine collagen induced arthritis.