C. ELEGANS MODEL FOR POLYGLUTAMINE TOXICITY

描述(摘自申请者摘要)：8种神经退行性疾病 是由蛋白质中谷氨酰胺束扩张引起的，包括脊髓 小脑性共济失调、DR解放军、亨廷顿病和肯尼迪病。它是 不清楚为什么扩大的聚谷氨酰胺区域是有毒的，而且没有治疗方法 治疗这些疾病。我们已经开发了一个线虫过度表达模型，用于 表达亨廷顿蛋白片段的多谷氨酰胺神经毒性 我们将评估突变型ataxin-1和ataxin-3的毒性活性 在这些线虫神经元中。PQE-1特异性强突变 增强多Q对线虫的毒性。我们将克隆并鉴定PQE-1。我们 将鉴定和克隆更多的增强子基因并鉴定， 鉴定和克隆抑制基因。相应的蛋白质是 亨廷顿病和其他疾病中多谷氨酸毒性的候选修饰物 多聚谷氨酰胺病。 我们将在线虫的Huntin、ataxin-1和Araxin-1的同源物中产生突变 Aaxin-3，以解决它们在神经系统和神经退行性变中的作用。 这些基因与多聚谷氨酰胺毒性、细胞凋亡的关系 将对通路和其他候选基因进行评估。我们会确认人类的身份 在我们的基因筛查中发现的增强基因和抑制基因的同源物 在其他模式生物中评估它们在多谷氨酰胺毒性中的作用 这些候选基因与人类疾病的相关性。

DESCRIPTION (From the Applicant's Abstract): Eight neurodegenerative diseases are caused by expansion of glutamine tracts in proteins, including spinal cerebellar ataxias, DRPLA, Huntington's disease and Kennedy's disease. It is unclear why expanded polyglutamine tracts are toxic and there is no treatment for these diseases. We have developed a C. elegans overexpression model for polyglutamine neurotoxicity by expressing huntingtin protein fragments in neurons and we will assess the toxic activity of mutant ataxin-1 and ataxin-3 in these same C. elegans neurons. Mutation of pqe-1 specifically and strongly enhances polyQ toxicity in C. elegans. We will clone and characterize pqe-1. We will characterize and clone additional enhancer genes and will identify, characterize and clone suppressor genes. The corresponding proteins are candidate modifiers of polyglutamines toxicity in Huntington's and other polyglutamine diseases. We will generate mutations in C. elegans homologs of huntintin, ataxin-1 and ataxin-3 to address their role in the nervous system and in neurodegeneration. The relationship between these genes, polyglutamine toxicity, the apoptotic pathway and other candidate genes will be assessed. We will identify human homologs of enhancer and suppressor genes identified in our genetic screens and assess their role in polyglutamine toxicity in other model organisms to address the relevance of these candidate genes to human disease.