The mechanism underlying the age-related failure of regeneration : new trial for successful neural regeneration

与年龄相关的再生失败的机制：成功神经再生的新试验

基本信息

批准号：
16500234
负责人：
KAWANO Hitoshi
金额：
$ 2.37万
依托单位：
Tokyo Metropolitan Organization for 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：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

To investigate the mechanism of the age-related failure of regeneration of transected axons, nigrostriatal dopaminergic axons were unilaterally transected in the lateral hypothalamus in adult mice and in immature mice aged postnatal days 7, 14 and 21. Ten days after the transection, tyrosine hydroxylase-immunoreactive axons had regenerated from caudal to rostral across the lesion site in mice transected at postnatal day 7, while they stopped and did not extend across the lesion site in mice transected at postnatal day 14 or older. Reactive astrocytes bearing chondroitin sulfate proteoglycans were observed around the lesion in mice transected at all ages. However, a fibrotic scar containing type IV collagen-immunoreactive deposits which was consistently formed at the lesion site in mice transected at postnatal day 14 or older, was not formed in mice lesioned at postnatal day 7. When 2,2'-dipyridyl, an inhibitor of collagen synthesis, was injected into the lesion site at the time of transection in both postnatal day 14 and adult mice, the deposition of type IV collagen and the formation of a fibrotic scar were completely prevented, and a large number of tyrosine hydroxylase-immunoreactive axons extended across the lesion and reinnervated the striatum. These results imply that the fibrotic scar formed in the lesion site is a crucial impediment to the regeneration of ascending dopaminergic axons in adult mice, and suggest that type IV collagen is required for the development of the fibrotic response to adult brain injury.

为了研究跨轴突再生的年龄相关失败的机制，成年小鼠的下丘脑和未成熟的小鼠在衰老的第7、14和21天，在下丘脑的外侧下丘脑中单方面透射。 - 免疫反应性轴突在产后第7天转移的小鼠的病变部位从尾部再生到tho骨，而它们停止，并未在14岁或以上的小鼠中延伸过小鼠的病变部位。在所有年龄段转移的小鼠的病变周围都观察到具有硫酸软骨蛋白聚糖的反应性星形胶质细胞。然而，在产后第7天，在第14天或以上的小鼠中未形成含有IV型胶原蛋白免疫反应性沉积物，在产后14岁或以上的小鼠的病变部位始终形成。胶原蛋白合成的抑制剂在出生后第14天和成年小鼠的横向时被注入病变部位，IV型胶原蛋白的沉积以及纤维化疤痕的形成得到了完全防止，并且大量酪氨酸羟化酶 - 羟化酶 - 羟化酶 - 免疫反应性轴突延伸到整个病变上，并加剧了纹状体。这些结果表明，在病变部位形成的纤维化疤痕是成年小鼠中升高多巴胺能轴突再生的关键障碍，并表明IV型胶原蛋白是对成人脑损伤的纤维化反应所必需的。