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

在动物中，大多数活化的T细胞在遇到抗原后迅速死亡。这一事件使动物摆脱了 过量淋巴细胞的负担，并降低动物自身免疫和淋巴肿瘤的风险。 已知这些细胞的死亡涉及与Bcl-2相关的蛋白质，然而，这些细胞死亡的方式与Bcl-2相关。 蛋白质相互作用并导致细胞死亡是未知的。同样，无反应性B细胞也具有缩短的 半衰期和最近的实验表明，这种现象也涉及Bcl-2家族的成员。 项目3中的实验将通过研究， Bcl-2蛋白家族成员之间的相互作用，因为T细胞从静止的，长寿的， 活化的、快速死亡的细胞和无反应性的B细胞。许多实验将集中在Bim，一种蛋白质 这对于发出淋巴细胞死亡信号非常重要，然而，也将进行研究以找出答案 当它不在的时候，什么代替它。此外，抗凋亡Bcl-2样蛋白的病毒类似物 将进行研究，因为这些蛋白质之一，虽然在T细胞中有活性，但似乎不能结合Bim。 就像Bcl-2一样此外，这些病毒类似物在T和B细胞中的作用不同，因此 对它们作用的实验可能揭示T细胞和B细胞死亡方式的重要差异。 最后，普遍认为淋巴细胞实际上被Executioner蛋白质巴克和 Bax的这些蛋白被认为是由其他促凋亡蛋白如Bim触发的。但 尽管多年的研究，Bim向巴克和Bax传递杀死信号的方法仍不清楚。 这个项目将跟进的想法，Bim触发巴克和Bax通过一个“打了就跑”的过程，与突变 以及对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.