NEUROPROTECTIVE BAX MUTANTS--MECHANISM AND UTILITY

神经保护性 BAX 突变体——机制和效用

• 批准号: 2839967
• 负责人: EUGENE M JOHNSON
• 金额: $ 24.52万
• 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/2839967
• 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（根据申请人的摘要改编）：偶然，申请人有 产生了一个截短的Bax突变体，结果证明是有效的抑制剂 神经元细胞凋亡。他的大部分申请将集中在这一发现上。他 将首先研究交感神经元成熟的机制 到非NGF依赖性状态；他提出了3个假设在此处进行测试：（a）损失 依赖性是由于改变 Bcl-2家族； （b）表达的蛋白质，该蛋白在细胞质中隔离bax 从而阻止其易位到线粒体；或（c）有一个 BAX的年龄依赖性后翻译后修饰。第二个特定目标 是扩展Bax截断突变体的结构 - 功能分析AS 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有抗凋亡。他的 第三个特定目的是查看截断的Bax是否也保护其他单元格类型， 包括大胶质细胞，成纤维细胞和淋巴细胞，抗细胞凋亡。具体的 AIM 4将测试截断的BAX是否将Bax易位 线粒体或线粒体中细胞色素c的损失。最后，与 研究人员是经验丰富的合作者，将生成TBAX转基因。