MORT1 IN APOPTOSIS OF MALIGNANT AND PRIMARY T CELLS

描述(改编自《调查者摘要》)：长期目标 这项拟议的研究的主要目的是了解细胞凋亡的机制。 恶性T细胞和原代T细胞。Fas是肿瘤坏死因子的成员 受体超家族，表达于活化的T细胞和许多 恶性细胞。抗Fas抗体诱导细胞凋亡 许多但不是所有的肿瘤细胞。类似的情况也可以在 不同发育阶段的T细胞。未成熟的T细胞是 特别容易受到Fas诱导的细胞凋亡，而成熟的T细胞 对抗Fas抗体的细胞凋亡作用有相当抵抗力。Mort 1 /FADD是一种带有死亡结构域的蛋白质，即蛋白质-蛋白质相互作用结构域 在Fas和肿瘤坏死因子的胞浆尾部也发现了这一点 受体P55。在敏感细胞中，抗Fas抗体的加入会触发 Mort1与Fas关联。这一关联过程的干扰由 显性负性Mort1蛋白导致细胞凋亡抑制。在……里面 几种对Fas介导的细胞凋亡具有抵抗力的恶性细胞株， Mortl被发现与Fas无关。因此，Mort1-Fas联合是一种 Fas诱导的细胞凋亡中的关键一步可能决定 细胞对抗Fas介导的细胞死亡。 淋巴瘤、胸腺瘤和T细胞杂交瘤以及转基因和 基因靶向突变小鼠将被用来了解Mortl在 恶性T细胞和原代T细胞的凋亡。以下是具体目标 建议。首先，将对Mort1蛋白的结构和功能进行分析 使用Fas/Mort1嵌合蛋白。第二，分子过程 恶性T细胞和原代T细胞中Mort1/Fas相关性的研究。 第三，将产生并分析Mortl缺陷小鼠。第四， Mort I及其相关蛋白在未成熟T细胞凋亡中的作用 将对细胞进行检查。 上述目标应有助于更好地理解 外周和中枢耐受以及为什么一些肿瘤细胞对 Fas诱导的细胞凋亡。所获得的信息可能会导致通过 在耐药的肿瘤细胞中可能诱导和阻止哪些细胞凋亡 癌症的发作。

DESCRIPTION (Adapted from the Investigator's Abstract): The long term goal of this proposed research is to understand the mechanisms of apoptosis in malignant and primary T cells. Fas is a member of the tumor necrosis factor receptor superfamily and is expressed on activated T cells and many malignant cells. Treatment with anti-Fas antibody leads to apoptosis in many but not all the tumor cells. A similar situation can also be found for T cells from different developmental stages. Immature T cells is particularly susceptible to Fas-induced apoptosis while mature T cells are quite resistant to the apoptotic-effect of anti-Fas antibodies. Mort 1 /FADD is a protein with a death domain, a protein-protein interaction domain that is also found in the cytoplasmic tail of Fas and tumor necrosis factor receptor p55. In sensitive cells, addition of anti-Fas antibodies triggers Mort1 to associate with Fas. Interference of this association process by a dominant negative Mort1 protein leads to inhibition of apoptosis. In several malignant cell lines that are resistant to Fas-mediated apoptosis, Mortl was found not to associate with Fas. Thus, Mortl-Fas association is a key step in Fas-induced apoptosis that might determine susceptibility of a cell to anti-Fas-mediated cell death. Lymphomas, thymomas and T cell hybridomas as well as transgenic and gene-targeted mutant mice will be used to understand the role of Mortl in apoptosis of malignant and primary T cells. The following specific aims are proposed. First, structure-function analysis of the Mortl protein will be performed using a Fas/Mortl chimeric protein. Second, the molecular process of Mortl/Fas association will be examined in malignant and primary T cells. Third, Mortl-deficient mice will be generated and analyzed. Fourth, the role of Mort I and one of its associating protein in apoptosis of immature T cells will be examined. The above aims should lead to a better understanding of the mechanisms of peripheral and central tolerance and why some tumor cells are resistant to Fas-induced apoptosis. The information obtained might lead to means by which apoptosis in resistant tumor cells might be induced and to halting of the onset of cancer.