MORT1 IN APOPTOSIS OF MALIGNANT AND PRIMARY T CELLS

描述（改编自研究者摘要）：长期目标 这项研究的目的是了解细胞凋亡的机制， 恶性肿瘤和原发性T细胞。 Fas是肿瘤坏死因子家族的一员 受体超家族，并在活化的T细胞和许多 恶性细胞 用抗Fas抗体治疗导致细胞凋亡， 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。 不成熟的T细胞 特别易受Fas诱导的凋亡的影响，而成熟的T细胞 对抗Fas抗体的促凋亡作用具有相当抗性。 死亡1 /FADD是一种具有死亡结构域的蛋白质， 也存在于Fas和肿瘤坏死因子的胞质尾区 p55受体。 在敏感细胞中，加入抗Fas抗体会触发 与Fas联系的Mort 1。这种关联过程的干扰， 显性负性Mort 1蛋白导致细胞凋亡的抑制。 在 几种对Fas介导的细胞凋亡有抗性的恶性细胞系， 莫特尔被发现与Fas无关。因此，Mortl-Fas协会是一个 Fas诱导细胞凋亡中可能决定A 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用于了解Mort 1在 恶性和原发性T细胞的凋亡。 具体目标如下： 提出了 首先，将对Mort 1蛋白的结构-功能分析进行分析。 使用Fas/Mort 1嵌合蛋白进行。 第二，分子过程 将在恶性和原代T细胞中检查Mort 1/Fas相关性。 第三，将产生并分析Mort 1缺陷型小鼠。 四是 Mort I及其相关蛋白在未成熟T细胞凋亡中的作用 将检查细胞。 上述目标应有助于更好地了解 外周和中枢耐受性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 诱导耐药肿瘤细胞凋亡， 癌症的发病

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.