27-羟基胆甾醇和脱氢表雄酮硫酸脂在SPG5A发病中作用机制的研究

Hereditary spastic paraplegia (HSP) is a common neurogenetic disease with relatively high disability. Mutations in CYP7B1 gene were identified responsible for autosomal recessive SPG5A. This mutated gene encodes an important hydroxylase which functions in the hydroxylation of 27-hydroxycholesterol as well as dehydroepiandrosterone(DHEA),whose predominant form in CNS is DHEA-sulfate (DHEAS).The detection of high levels of 27-hydroxycholesterol and DHEAS in cerebrospinal fluid of SPG5A patients revealed that these two are closely associated with SPG5A. 27-hydroxycholesterol and DHEAS could result in cell apoptosis by suppressing Akt/PI3K(phosphoinositide 3-kinase) cascade, a signaling pathway important for cell survival, and thus interfering the development of neurite. However, how these two to regulate the Akt/PI3K cascade thus causing SPG5A still remains unknown. As a new biomarker, neurosteroids has been valued but there has been barely research focused on its role in mechanism of HSP. In this project, by applying molecular and cell biology methods like two dimensional fluorescent difference gel electrophoresis(2D-DIGE), Protein patterns,etc, we would explore the targets and the signaling pathways of 27-hydroxycholesterol and DHEAS in the mechanism of SPG5A on the basis of previous researches, and expect to offer the clinical as well as laboratory evidence for the identification of the mechanism of SPG5A and the discovery of effective therapeutic targets in SPG5A.

遗传性痉挛性截瘫是一种较为常见的神经遗传疾病。CYP7B1是SPG5A的致病基因,是一种重要的羟基化反应酶,参与27-羟基胆甾醇和脱氢表雄酮(DHEA)的羟基化反应,DHEA主要以脱氢表雄酮硫酸脂(DHEAS)形式存在。SPG5A患者脑脊液中27-羟基胆甾醇和DHEAS明显增高,提示其与SPG5A发病存在密切联系。27-羟基胆甾醇和DHEAS能促使细胞凋亡,抑制PI3K/Akt信号通路,影响神经突生长,但具体通过哪些靶点来调节PI3K/Akt信号通路,导致SPG5A发病还不明确。作为一种新的生物学标记物,神经甾体越来越受研究者们的重视,但其在HSP发病机制中的研究却是个空白。本课题希望在以往的相关工作基础上,运用双向荧光差异凝胶电泳等方法,探索27-羟基胆甾醇和DHEAS是通过哪些靶点及信号通路来产生致病作用,为最终明确SPG5A发病机制,寻找有效治疗靶点提供临床和实验室依据

遗传性痉挛性截瘫是一种较为常见的神经遗传疾病。CYP7B1是SPG5A的致病基因，编码一种重要的羟基化反应酶，参与27-羟基胆甾醇和脱氢表雄酮（DHEA）的羟化反应，DHEA主要以脱氢表雄酮硫酸酯（DHEAS）的形式存在。SPG5A患者脑脊液中27-羟基胆甾醇与DHEAS明显增高，提示其与SPG5A发病存在密切关系，然而其致病机制尚未明确。通过体内外研究表明：1.DHEAS通过抑制σ1受体（σ1R）活化，影响PI3K/Akt信号通路的激活，从而引起运动神经元的凋亡；2.CYP7B1-/-小鼠体内存在轴索逆向运输功能障碍，导致其轴索形态学的一系列改变，最终导致其痉挛性截瘫表型的发生。

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