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，p38和JNK MAP激酶通路在Th 1细胞中被TCR刺激显著激活，但在Th 2细胞中不被激活。这些数据表明，p38/JNK MAP激酶途径在辅助性T细胞中的调节取决于细胞环境。初步数据显示GADD 45 γ和GADD 45 β在Th 1细胞中相对于Th 2细胞高度表达。由于GADD 45家族蛋白在COS-7细胞中过表达时显示激活JNK和p38，因此他们假设这些分子负责Th 1细胞中p38和JNK活性的升高，并且可能对Th 1细胞的功能至关重要。与该假设一致，在Th 1细胞中，GADD 45 γ的缺失显著提高了TCR刺激的p38和JNKs活化的阈值。此外，GADD 45 γ还介导Th 1功能，如IFN-γ产生和迟发型超敏反应。除了它们在Th 1细胞功能中的作用外，他们还发现GADD 45 β在滑膜细胞中由TNF-α诱导。因此，他们假设GADD 45家族分子可能通过炎性细胞因子调节滑膜细胞中p38/JNK MAP激酶通路的激活。由于p38/JNK MAP激酶通路参与了类风湿性关节炎的发病机制，他们假设GADD 45家族蛋白参与了此类疾病的发展。为了进一步研究GADD 45通路在介导p38/JNK MAP激酶活化中的作用及其与类风湿性关节炎的相关性，他们提出： 目标1.利用遗传学和生物信息学方法研究GADD 45通路在介导TCR刺激中的作用。 目标二。研究GADD 45蛋白在介导细胞因子激活p38/JNK MAP激酶通路中的作用。 目标3：研究GADD 45 γ、GADD 45 β、MEKK 4基因突变在小鼠胶原诱导性关节炎中的作用。

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.