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    题名: 以瑞特氏症模式小鼠研究運動障礙之療癒—目標紋狀體
    In Search of Interventions to Ameliorate Motor Deficits in Mouse Models of Rett Syndrome: Targeting to the Striatum
    作者: 廖文霖
    贡献者: 神科所
    关键词: 瑞特氏症;第二型甲基 CpG 結合蛋白;紋狀體;多巴胺;L-多巴;移植
    Rett syndrome;Methyl-CpG binding protein 2 (MeCP2);Striatum;Dopamine L-DOPA;Transplantation
    日期: 2017-01
    上传时间: 2025-05-29 11:56:50 (UTC+8)
    摘要: 瑞特氏症 (Rett Syndrome, RTT) 是由第二型甲基 CpG 結合蛋白 (methyl-CpG binding protein 2, MeCP2) 之基因突變所導致的一種神經發育疾病，患者多出現嚴重的運動障礙。究竟為何一個廣泛表現在全身的轉錄因子-MeCP2 的缺失會造成運動障礙，目前仍無解答。我們先前的研究發現，MeCP2 缺失小鼠的運動障礙會伴隨紋狀體分子與細胞表型的改變 (國科會計畫編號 NSC99-2320-B-004-001-MY2；Kao et al., 2013)，而且紋狀體前端的 MeCP2 在多巴胺所主導的運動控制中扮演必要且充要的角色（國科會計畫編號 NSC101-2320-B-004-003-MY2）。我們目前的研究進一步顯示，紋狀體前端很可能是 RTT 運動障礙之病灶所在，可能成為治療時的投藥目標區。由於目前尚未釐清是否由於紋狀體前端的多巴胺不足而導致 RTT 的運動障礙，我們因此於本計劃中嘗試利用腦內注射多巴胺前驅物Ｌ-DOPA (Aim 1) 或移植多巴胺前驅細胞(Aim 2) 來提升紋狀體前端多巴胺的含量，並測試其是否可恢復 MeCP2 缺失小鼠的運動功能。本研究之成果 將不只增加我們對於 RTT 運動障礙在神經化學及神經解剖成因的瞭解，也可望提供具體可行的治療方法減輕 RTT 的運動障礙。
    Rett Syndrome (RTT), caused by mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene, is an neurodevelopmental disorder with striking motor deficits. How loss-of-function of a widely expressed transcription regulator, MeCP2, leads to characteristic motor dysfunction in RTT remains poorly understood. We previously found that psychomotor deficits in Mecp2-null mice are associated with aberrant molecular and cellular phenotypes in the striatum (NSC-99-2320-B-004-001-MY2; Kao et al., 2013), and that MeCP2 in the rostral striatum is necessary and sufficient for dopamine-mediated motor control (NSC-101-2320-B-004-003-MY2). Our current findings further suggest that the rostral striatum could be a critical focus of motor deficits in RTT, serving as a potential target brain region for therapeutic interventions. It remains to be address whether deficient dopamine content in the rostral striatum plays a key role to cause psychomotor deficits in RTT-like mice. Here we propose to rescue dopamine content by brain infusion of dopamine precursor, L-DOPA (Aim 1) or by grafting dopaminergic precursor cells (Aim 2) into the rostral striatum and examine the restoration effects on psychomotor function in mice lacking MeCP2. Our findings will provide not only a neurochemical/ neuroanatomical origin of motor deficits in RTT, but also therapeutic strategies to ameliorate psychomotor dysfunction in RTT.
    關聯: 科技部, MOST103-2320-B004-001-MY2, 103.08-105.07
    数据类型: report
    显示于类别:[神經科學研究所] 國科會研究計畫

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