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

Bcl-2相关蛋白在活化T细胞死亡中的功能

• 批准号: 7188251
• 负责人: Philippa C. Marrack
• 金额: $ 24.13万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7188251
• 关键词: Affect; Animals; Antigens; Apoptosis; Apoptotic; Autoimmunity; B-Lymphocytes; Bax protein; Binding; Cause of Death; Cell Death; Cells; Cessation of life; Event; Family; Goals; Half-Life; Homeostasis; Life; Lymphocyte; Measurement; Process; Protein Family; Proteins; Relative (related person); Rest; Risk; Role; Running; Signal Transduction; T-Lymphocyte; Testing; Thinking; Viral; analog; autoreactive B cell; bak protein; cell killing; cell type; follow-up; interest; killings; lymphoid neoplasm; member; pro-apoptotic protein; programs; research study; response

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.

在动物体内遇到抗原后，大多数活化的 T 细胞会迅速死亡。这个活动减轻了动物的负担 减轻过多淋巴细胞的负担，并降低动物患自身免疫性疾病和淋巴肿瘤的风险。 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 蛋白质相互作用并导致细胞死亡尚不清楚。同样，无反应的 B 细胞也有缩短的 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数量的变化来研究这些问题，并且 当 T 细胞从休眠、长寿命状态转变为 Bcl-2 蛋白质家族成员之间的相互作用时， 激活、快速死亡的细胞和无反应的 B 细胞。许多实验将集中在 Bim，一种蛋白质 这对于向淋巴细胞发出死亡信号非常重要，但是，还将进行研究以找出答案 当 Bim 不存在时，用什么替代它。此外，抗凋亡 Bcl-2 样蛋白的病毒类似物 将会被研究，因为这些蛋白质之一虽然在 T 细胞中活跃，但似乎不能结合 Bim 与 Bcl-2 的作用相同。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 关于它们作用的实验可能会揭示 T 细胞和 B 细胞死亡方式之间的重要差异。 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。这些蛋白质被认为是由其他促凋亡蛋白质（例如 Bim）触发的。然而， 尽管经过多年的研究，Bim 向 Bak 和 Bax 传递杀戮信号的方式仍不清楚。 该项目将延续 Bim 通过“肇事逃逸”过程触发 Bak 和 Bax 的想法，并通过突变 以及对刽子手和 Bim 的结构研究。