雌激素对遗传性痉挛性截瘫第4型（SPG4）发病的影响及机制研究

Hereditary spastic paraplegia type 4 (SPG4) is the most common subtype of autosomal dominant hereditary spastic paraplegia, which is caused by the mutation of SPAST gene. SPAST encode the protein of spastin and the loss of function of spastin is closely related to the pathogenesis of SPG4. We found there are much less female SPG4 patients than males in China and female SPG4 patients were much less serious than male patients. In previous study, we found microtubule and endoplasmic reticulum morphology change in SPAST knockout cells, and estradiol can rescue this damage. These results suggest that estrogen may be able to alleviate the abnormal phenotype caused by the loss of function of spastin through a certain mechanism. According to this hypothesis, we intend to apply SPAST knockout cells and mouse model, and the technique of gene knockout, transfection and so on , thoroughly from the levels of the organism, cell and molecule, to systematically study the protection effect of estrogen on SPG4 models and to further elucidate the molecular mechanism.

遗传性痉挛性截瘫第4型（SPG4）是常染色体显性遗传性痉挛性截瘫最常见亚型，SPAST是其致病基因，其编码蛋白spastin功能缺失与SPG4的发病密切相关。申请者所在研究组发现在中国人群中女性患者明显少于男性，并且女性患者症状明显比男性轻。且我们前期研究发现在SPAST基因敲除细胞中微管及内质网形态改变，而17-β雌二醇可以改善这一损伤。这些结果提示我们雌激素或许可以通过某种机制，缓解spastin功能缺失导致的异常表型。根据这一假设，本项目拟采用SPAST基因敲除的体外细胞模型、小鼠模型，结合基因敲除、基因转染等实验技术手段，从整体、细胞和分子三个层面上深入、系统的研究雌激素对SPG4模型的保护作用，并阐明其具体的分子机制。