NEUROPROTECTIVE BAX MUTANTS--MECHANISM AND UTILITY

描述（改编自申请人的摘要）：碰巧，申请人有 产生了一个截短的Bax突变体，它被证明是一个有效的抑制因子， 神经元凋亡的过程他的大部分申请将集中在这一发现上。他 将开始研究交感神经元成熟的机制 到非神经生长因子依赖状态;他提出了3个假设来测试这里：（a）损失 依赖性是由于成员的表达模式的改变， BCL-2家族;（B）表达在细胞质中螯合BAX的蛋白， 从而防止其易位到线粒体;或（c）存在 BAX的年龄依赖性翻译后修饰。第二个具体目标 将Bax截短突变体的结构-功能分析扩展为 神经元凋亡的抑制因子。他还将确定截短突变体 BCL-2家族的其他促凋亡成员是抗凋亡的。他 第三个具体目的是观察截短的BAX是否也保护其它细胞类型， 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 目的4将测试截短的Bax是否阻断BAX易位到 线粒体中的细胞色素c或细胞色素c的丢失。最后以 一个有经验的合作者，研究者将产生tBAX转基因。

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.