NEUROPROTECTIVE BAX MUTANTS--MECHANISM AND UTILITY

神经保护性 BAX 突变体——机制和效用

• 批准号: 6187941
• 负责人: EUGENE M JOHNSON
• 金额: $ 24.03万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-10 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6187941
• 关键词: BCL2 gene /protein; apoptosis; cell type; cytochrome c; fibroblasts; genetically modified animals; glia; laboratory mouse; lymphocyte; neuroprotectants; posttranslational modifications; suppressor mutations; sympathetic nervous system

DESCRIPTION (Adapted from applicant's abstract): By chance, the applicant has produced a truncated mutant of Bax, which turned out to be a potent suppressor of neuronal apoptosis. Much of his application will focus on this finding. He will begin by investigating the mechanism by which sympathetic neurons mature to a non-NGF dependent state; he proposes 3 hypotheses to test here: (a) loss of dependence is due to an alteration in pattern of expression of members of the BCL-2 family; (b) a protein is expressed that sequesters BAX in cytoplasm, thus preventing its translocation to the mitochondria; or (c) there is an age-dependent post-translational modification of BAX. The second specific aim is to extend structure-function analysis of truncation mutants of Bax as suppressors of neuronal apoptosis. He will also determine if truncation mutants of other pro-apoptotic members of the BCL-2 family are anti-apoptotic. His third specific aim is see if truncated BAX also protects other cell types, including macroglia, fibroblasts, and lymphocytes, against apoptosis. Specific aim 4 will test whether truncated Bax blocks translocation of BAX to the mitochondria, or the loss of cytochrome c from the mitochondria. Finally, with an experienced collaborator, the investigator will generate tBAX transgenics.

描述（改编自申请人的摘要）： 申请人偶然有 产生了 Bax 的截短突变体，结果证明它是一种有效的抑制因子 神经元凋亡。他的大部分申请将集中在这一发现上。他 首先将研究交感神经元成熟的机制 至非 NGF 依赖状态；他提出了 3 个假设来检验：(a) 损失 依赖性的产生是由于成员表达模式的改变 BCL-2家族； (b) 表达将 BAX 隔离在细胞质中的蛋白质， 从而防止其易位至线粒体；或 (c) 有一个 BAX 的年龄依赖性翻译后修饰。第二个具体目标 是将 Bax 截短突变体的结构功能分析扩展为 神经元凋亡的抑制剂。他还将确定截断突变体是否 BCL-2 家族的其他促凋亡成员具有抗凋亡作用。他的 第三个具体目标是看看截短的 BAX 是否也能保护其他细胞类型， 包括大胶质细胞、成纤维细胞和淋巴细胞，对抗细胞凋亡。具体的 目标 4 将测试截短的 Bax 是否会阻止 BAX 易位到 线粒体，或线粒体中细胞色素 c 的损失。最后，与 作为一名经验丰富的合作者，研究人员将产生 tBAX 转基因。