Functions of Bcl-2 Related Proteins in Activated T Cell Death

大多数被激活的T细胞在与动物体内的抗原相遇后会迅速死亡。这一事件使这种动物摆脱了 减少过量淋巴细胞的负担，降低动物患自身免疫和淋巴样肿瘤的风险。 已知这些细胞的死亡涉及与Bcl-2相关的蛋白质，然而，这些 蛋白质相互作用并导致细胞死亡尚不清楚。同样，无能B细胞也有一个缩短的 半衰期和最近的实验表明，这种现象也涉及到Bcl-2家族的成员。 项目3中的实验将通过研究数量的变化来研究这些问题，并 当T细胞从静息的、长寿的转化为 激活的、迅速死亡的细胞和无能的B细胞。许多实验将集中在Bim，一种蛋白质 这在通知淋巴细胞死亡方面非常重要，然而，也将进行研究以找出 当BIM不在时，用什么来替代它。此外，抗细胞凋亡的Bcl2样蛋白的病毒类似物 将进行研究，因为其中一种蛋白质虽然在T细胞中活性很高，但似乎不能与Bim结合 与Bcl2的作用方式相同。此外，这些病毒类似物在T细胞和B细胞中的作用不同，因此 对它们作用的实验可能会揭示T细胞和B细胞死亡方式的重要差异。 最后，人们普遍认为，淋巴细胞实际上是被刽子手蛋白、Bak和 巴克斯。这些蛋白被认为是由Bim等其他促凋亡蛋白触发的。然而， 尽管经过多年的研究，但比姆向贝克和巴克斯传递杀戮信号的方式尚不清楚。 该项目将跟进的想法，即BIM触发Bak和BAX通过“打了就跑”的过程，与突变 以及关于刽子手和比姆的结构研究。

After encounter with antigen in animals most activated T cells die rapidly. This event relieves the animal of the burden of excess lymphocytes and reduces the risk to the animal of autoimmunity and lymphoid tumors. The death of these cells is known to involve proteins related to Bcl-2, however, the way in which these proteins interact and cause the cells to die is not known. Likewise, anergic B cells also have a shortened half life and recent experiments that this phenomenon also involves members of the Bcl-2 family. Experiments in Project 3 will investigate these problems by studying the changes in amount of, and interactions between, members of the Bcl-2 family of proteins as T cells convert from resting, long lived, to activated, rapidly dying, cells and in anergic B cells. Many of the experiments will focus on Bim, a protein which is very important in signaling lymphocytes to die, however, studies will also be performed to find out what substitutes for Bim when it is absent. In addition, viral analogs of the anti-apoptotic Bcl-2-like proteins will be studied, since one of these proteins, though active in T cells, does not seem to be able to bind Bim in the same way as Bcl-2 does. Moreover, these viral analogs act differently in T and B cells, therefore experiments on their action may reveal important differences between the ways T and B cells die. Finally, it is generally agreed that lymphocytes are actually killed by the Executioner proteins, Bak and Bax. These proteins are thought to be triggered by other pro-apoptotic proteins such as Bim. However, the means whereby Bim delivers the signal to kill to Bak and Bax is not known in spite of many years of study. This Project will follow up the idea that Bim triggers Bak and Bax via a "hit and run" process, with mutational and structural studies on the Executioners and Bim.