CAV-1蛋白介导甲状腺功能减退型脑白质损伤的机理研究

Normal thyroid function is necessary for the maintenance of cerebral white matter structure. Our clinical data showed that hypothyroid status was related to the presence of leukoaraiosis and its severity in patients. We established hypothyroid mice and oligodendroglial model in the preliminary experiments. Hypothyroid mice demonstrated significant myelin loss in corpus callosum, while hypothyroid oligodendrocytes illustrated immature appearance and myelin malformation. It was confirmed that CAV-1 expression can be induced by the combination between thyroid hormones and TRα receptor. Moreover, CAV-1 can interact with Ras in oligodendrocytes. With animal and oligodendroglial model under wild type and knock-out background, we aim to investigate the effect of CAV-1 in hypothyroidism-induced white matter injury, the function of supplementation of LV-Cav-1 or CSD in white matter improvements and the underlying molecular signaling. This project may unveil the pathogenesis of hypothyroidism-induced white matter injury with the involvement of oligodendroglial CAV-1 and downstream signals, as well as provide possible approaches for the management of hypothyroidism-induced white matter injury.

甲状腺功能对脑白质结构的维持十分重要。我们前期在临床上发现甲状腺功能减退患者与脑白质疏松的发生及其严重程度有关。为此，在预实验中我们建立了甲功减退体内外模型，证实了甲功减退能够导致小鼠胼胝体区髓鞘脱失、少突胶质细胞成熟障碍和髓鞘化能力受损。我们还发现甲状腺激素可通过与核受体TRα结合诱导少突胶质细胞CAV-1蛋白表达，后者可与胞内Ras蛋白产生交互作用。为全面探究甲功减退导致脑白质损伤相关机制，本课题拟从体内外两个水平、野生和基因敲除两个层面探讨CAV-1蛋白参与到甲状腺功能减退型脑白质损伤中的可能分子途径，最后结合外源性给予LV-Cav-1及CSD功能性多肽进一步了解其在脑白质损伤中的作用。论证甲状腺功能减退导致少突胶质细胞CAV-1蛋白表达减少，破坏其与下游信号分子交互作用从而导致脑白质损伤的发生，为甲状腺功能减退型脑白质损伤的发病机制提供思路，为其防治提供理论依据。

甲状腺功能对脑白质结构的维持十分重要，甲状腺功能减退可引起髓鞘损害，而其具体的分子机制还不清楚。少突胶质细胞CAV-1参与髓鞘糖蛋白的锚定和细胞内信号转导，然而其是否介导甲状腺功能减退相关髓鞘脱失也不清楚。我们通过PTU/LID饮食建立小鼠甲状腺功能减退模型，通过去除促分化液中的T3构建体外甲状腺功能减退模型。在体内外模型中，少突胶质细胞CAV-1表达水平显著降低，OPC分化及成髓鞘能力均受到抑制。临床脑白质疏松患者的血清CAV-1水平也显著降低。Cav-1-/-小鼠胼胝体髓鞘化水平低于野生小鼠，Cav-1-/- OPC分化能力受限。而给予Cav-1过表达病毒能够显著改善甲状腺功能减退相关的脱髓鞘改变，促进OPC分化和成熟髓鞘蛋白表达。在甲状腺功能减退模型中，少突胶质细胞TRα表达显著减少，可能是造成少突Cav-1表达减少及髓鞘损伤的上游机制。而CAV-1的髓鞘保护作用依赖于其与胞内Ras分子的交互及下游Raf/ERK通路的激活，因此，Ras/Raf/ERK通路可能是少突胶质细胞CAV-1维系髓鞘结构的下游通路。综上所述，课题论证了甲状腺功能减退引起少突胶质细胞CAV-1蛋白表达减少，从而导致脑白质损伤发生的上下游机制，为甲状腺功能减退相关脑白质损伤的防治提供思路和理论依据。