帕金森病大鼠模型中转基因表达对多巴胺水平的调控研究  

Regulation of dopamine levels by transgene expression in rat models of Parkinson's disease

作　　者：李小刚[1] 樊东升[1] 肖卫忠[1] 沈扬[1] 村松慎一 小泽敬也[2] 中野今治 

机构地区：[1]北京大学第三医院神经内科,北京100083 [2]日本枥木县自治医科大学神经内科

出　　处：《中华神经医学杂志》2007年第12期1197-1201,共5页Chinese Journal of Neuromedicine

摘　　要：目的究设计一种病毒载体介导的体内调节系统,依据诱导性Cre重组酶来调控转基因治疗帕金森病大鼠的基因表达。方法将重组腺相关病毒(AAV)载体表达的Cre重组酶融合到雌激素受体的配体结合区,与AAV载体表达的多巴胺合成酶一起转导到帕金森病大鼠模型中。用合成的雌激素受体调节剂他莫昔芬处理。结果诱导位于LoxP侧面的酪氨酸羟化酶(TH)序列选择性的敲掉,导致多巴胺的合成减少,而芳香族氨基酸脱羧酶(AADC)的表达不受影响,从而保持左旋多巴的疗效。结论病毒载体介导的诱导性的Cre重组酶在体内的应用可作为一种分子开关,对转基因表达进行时空调控,从而增加基因治疗的安全性。Objective To develop a viral vector-mediated somatic regulation system based on inducible Cre recombinase to regulate transgene expression for the treatment of rats with Parkinson＇s disease （PD）. Methods Cre recombinase expressed by recombinant adeno-associated virus （AAV） vectors was fused to the ligand-binding domain of the estrogen receptor and transduced with dopamine-synthesizing enzymes expressed by AAV vectors into rat PD models. Tamoxifen, a synthetic estrogen receptor modulator, was applied to treat the rat models. Results Tamoxifen induced selective knockout oftyrosinehydroxylase （TH） sequences flakingX-overofP1 （loxP） sites, resulting inthe reduction of dopamine synthesis, but not affecting the expression of aromatic L-amino acid decarboxylase （AADC）, and thus maintained the efficacy of L-dopa. Conclusion The application of viral vector-mediated inducible Cre recombinase can be regarded as an in vivo molecular switch that allows spatial and temporal regulation of transgene expression for the enhancement of safety in gene therapy.

关 键 词：帕金森病 腺相关病毒 基因调控 CRE重组酶 多巴胺 

分 类 号：R742.5[医药卫生—神经病学与精神病学]