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Adenoviral gene transfer of neurotrophic factors to injured adult motoneurons

神经营养因子的腺病毒基因转移至受损的成年运动神经元

基本信息

批准号：
12670636
负责人：
WATABE Kazuhiko
金额：
$ 1.98万
依托单位：
TOKYO METROPOLITAN ORGANIZATION OF MEDICAL RESEARCH
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

We examined neuroprotective effects of recombinant adenoviral vectors encoding glial cell linederived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT 1), transforming growth factor-β2 (TGFβ2), and insulin-like growth factor-1 (IGF1) on lesioned adult rat facial motoneurons. The right facial nerves of adult Fischer 344 male rats were avulsed and removed from the stylomastoid foramen, and adenoviral vectors were injected into the facial canal. Animals avulsed and treated with adenovirus encoding GDNF, BDNF, CNTF, CT1, TGFβ2 and IGF1 showed intense immunolabeling for these factors in lesioned facial motoneurons, respectively, indicating adenoviral induction of the neurotrophic factors in these neurons. The treatment with adenovirus encoding GDNF, BDNF or TGFβ2 after avulsion significantly prevented the loss of lesioned facial motoneurons, improved choline acetyltransferase immunoreactivity and prevented the induction of nitric oxide synthase activity in these neurons. The treatment with adenovirus encoding CNTF, CT1 or IGF1, however, failed to protect these neurons after avulsion. These results indicate that adenovirus-mediated gene transfer of GDNF and BDNF and TGFβ2 but not CNTF, CT1 or IGF1 may prevent the degeneration of motoneurons in adult humans with motoneuron injury and motor neuron diseases.

本实验观察了携带胶质细胞源性神经营养因子、脑源性神经营养因子、睫状神经营养因子、心肌营养素-1、转化生长因子-β-2和胰岛素样生长因子-1基因的重组腺病毒载体对损伤成年大鼠面运动神经元的神经保护作用。取成年Fischer 344只雄性大鼠右侧面神经，从茎乳突孔取出，将腺病毒载体注入面神经管内。神经营养因子、CT1、转化生长因子β-2和胰岛素样生长因子1的腺病毒感染组动物损伤面运动神经元中均有较强的免疫标记，表明这些神经营养因子在这些神经元中腺病毒的诱导作用。撕脱伤后应用携带胶质细胞源性神经营养因子、神经营养因子或转化生长因子β-2的腺病毒治疗可明显阻止受损运动神经元的丢失，改善胆碱乙酰转移酶的免疫反应，并阻止一氧化氮合酶在这些神经元中的活性诱导。然而，携带CNTF、CT1或IGF1的腺病毒治疗不能保护撕脱后的这些神经元。这些结果表明，腺病毒介导的神经营养因子、神经营养因子和转化生长因子β-2基因转移可以预防运动神经元损伤和运动神经元病患者运动神经元的变性。