九种多聚谷氨酰胺疾病之一的17型小脑脊髓共济失调（Spinocerebellar ataxia 17，SCA17）是因TATA盒结合蛋白（TATA box-binding protein，TBP）多聚谷氨酰胺异常扩增所致的遗传性神经退行性疾病。机体普遍表达的突变TBP(mTBP)如何导致以小脑萎缩和Purkinje细胞缺失为特征的SCA17一直是研究热点。少突胶质细胞对维持脑功能起重要作用。但是在少突胶质细胞表达的mTBP蛋白是否和怎样导致SCA17 的神经性症状仍不清楚。本课题拟运用loxp/cre重组系统建立选择性在少突胶质细胞表达mTBP的KI小鼠模型并结合SCA17KI小鼠模型、表达mTBP的少突胶质细胞培养及其与原代神经元混合培养，综合运用动物行为学、免疫组织化学，细胞及分子生物学技术，明确表达mTBP的少突胶质细胞在SCA17发病中的作用，为多聚谷氨酰胺疾病诊疗提供新的靶点。

The polyglutamine diseases consist of nine neurodegenerative disorders including spinocerebellar ataxia type 17（SCA17）that is caused by a polyglutamine tract expansion in the TATA box-binding protein(TBP). How ubiquitously expressed polyglutamine-expanded mutant TBP(mTBP) proteins can selectivly cause marked cerebellar atrophy and Purkinje cell loss still under investigation. It became increasingly evident that oligodendrocytes accomplish a more important role in brain function than previously thought.It remains largely unknown whether and how mTBP in oligodendrocyte can contribute to the neurological symptoms of SCA17.As in this proposal, we intend to establish a new knock-in mouse model that selectively expresses mutant TBP in oligodendrocytes via loxp/cre recombination system. we will also express mTBP in oligodendrocytes in vitro and culture these cells with or without neurons.we intend to use animal behavioral study, immnohistochemisty, cell and molecular biology strategies to determine the role of mTBP expressed oligodendrocytes in the pathogenesis of SCA17. This study will allow us to discover some oligodendrocyte dependent neurological symptoms of polyQ-expansion diseases, which are usually characterized by mutant protein neurotoxicity, and shed light on the underlying mechanisms.This study will also provide new targets for developing diagnostical and therapeutical strategies.