Mouse Model and Interactors for Machado Joseph Disease

马查多约瑟夫病的小鼠模型和相互作用器

• 批准号: 6419061
• 负责人: VERONICA COLOMER
• 金额: $ 36.79万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6419061
• 关键词: brain metabolism; cerebellar ataxia /dyskinesia; disease /disorder model; genetically modified animals; homopeptide; human tissue; immunocytochemistry; intermolecular interaction; laboratory mouse; model design /development; mutant; nerve /myelin protein; protein metabolism; protein sequence; proteolysis; western blottings; yeast two hybrid system

DESCRIPTION (Adapted from applicant's abstract): Machado Joseph disease (MJD), or spinocerebellar ataxia-3 (SCA-3), is the most common dominant spinocerebellar ataxia. MJD/SCA-3 is hereditary, neurodegenerative, and caused by glutamine expansion in the protein ataxin-3 (mutant ataxin-3) possibly resulting in a gain of function. The applicant's aim is to understand the mechanism(s) of neurodegeneration in MJD/SCA-3. SPECIFIC Aim #1: To facilitate the study MJD/SCA-3, the investigator will develop a mouse model. Transgenic mice were generated expressing human full-length mutant ataxin-3. The investigator will define the time course of behavior abnormalities and age at death. There will be a search for evidence of neurodegeneration. SPECIFIC Aim #2: The investigator will test the hypothesis that neurodegeneration is caused by a proteolytic event forming a toxic fragment. A small form of mutant ataxin-3 in transgenic mouse brain was identified. Its brain distribution will be determined. The putative cleavage site will be identified. The investigator will study transgenic mice expressing mutant ataxin-3 with the putative cleavage site mutated. SPECIFIC Aim #3: The applicant's aim is to test the hypothesis that mutant ataxin-3 interactors cause neurodegeneration. A mutant ataxin-3 interactor using the yeast-two-hybrid method was identified. The investigator will determine if the interaction occurs in mammalian cells and search/characterize for new interactors.

描述（改编自申请人摘要）：马查多约瑟夫病（MJD）， 或脊髓小脑性共济失调-3（SCA-3），是最常见的显性 脊髓小脑性共济失调MJD/SCA-3是遗传性的，神经退行性的， 通过蛋白质共济失调蛋白-3（突变型共济失调蛋白-3）中的谷氨酰胺扩增， 导致功能的增益。申请人的目的是了解 MJD/SCA-3中神经变性的机制。 具体目标#1：为了促进研究MJD/SCA-3，研究者将 建立小鼠模型。产生表达人类的转基因小鼠。 全长突变型共济失调蛋白-3。研究者将定义 行为异常和死亡年龄会有一场搜查 神经变性 具体目标#2：研究者将检验以下假设： 神经变性是由形成毒性片段的蛋白水解事件引起的。一 在转基因小鼠脑中鉴定了小形式的突变型共济失调蛋白-3。其 大脑的分布将被确定。推定的切割位点将是 鉴定研究者将研究表达突变体的转基因小鼠， 具有突变的假定切割位点的共济失调蛋白-3。 具体目的#3：申请人的目的是检验突变体 共济失调蛋白-3相互作用物引起神经变性。一种突变型共济失调蛋白-3相互作用因子 用酵母双杂交法进行了鉴定。研究者将 确定相互作用是否发生在哺乳动物细胞中，并搜索/表征 for new新interactors互动.