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NEUROPROTECTIVE BAX MUTANTS--MECHANISM AND UTILITY

神经保护性 BAX 突变体——机制和效用

基本信息

批准号：
6639571
负责人：
EUGENE M JOHNSON
金额：
$ 25.86万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/6639571
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

项目摘要

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(改编自申请者摘要)：一次偶然的机会，申请者产生了bax的截短突变体，事实证明它是一个有效的抑制子神经细胞的凋亡。他的大部分申请都将集中在这一发现上。他将从研究交感神经元成熟的机制开始到非NGF依赖状态；他提出了3个假设来检验：(A)损失依赖的原因是由于以下成员表达模式的改变 BCL-2家族；(B)表达一种将Bax隔离在细胞质中的蛋白质，从而阻止其移位到线粒体；或(C)存在 BAX的年龄依赖性翻译后修饰。第二个具体目标是扩展Bax AS截断突变体的结构-功能分析神经细胞凋亡的抑制因子。他还将确定截断突变体 BCL-2家族中其他促凋亡成员中的大多数是抗凋亡的。他的第三个具体目的是看看截短的BAX是否也保护了其他类型的细胞，包括巨胶质细胞、成纤维细胞和淋巴细胞，抗细胞凋亡。特定的目标4将测试截短的BAX是否阻止BAX易位到线粒体，或从线粒体中失去细胞色素c。最后，有了作为一名经验丰富的合作者，这位研究员将产生tBAX转基因药物。