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PROTECTION FROM DEATH OF AXOTOMIZED RETINAL GANGLION CELLS AND PROMOTION OF THEIR AXONAL REGENERATION

防止轴切视网膜神经节细胞死亡并促进其轴突再生

基本信息

批准号：
12671733
负责人：
WATANABE Masami
金额：
$ 2.37万
依托单位：
INSTITUTE FOR DEVELOPMENTAL 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 2002
项目状态：
已结题

项目摘要

Retinal ganglion cells (RGCs) of mammals regenerate their axons into a grafted peripheral nerve segment, but numbers of regenerated RGCs are 2% in average. They are too small to intend functional recovery of impaired vision, or to guide axons of stem cell-derived RGCs into the central visual areas. Therefore, methods increasing the numbers should be developed. We tested several drugs which protect death of axotomized RGCs since survival of axotomized RGCs is the first requisite for axonal regeneration. We also obtained rate of axonal regeneration.1. To develop a method promoting RGC survival, survival curve of axotomized RGCs were examined. Beta cells degenerate rapidly between day 3 to 7, while alpha cells did slowly until day 14. Death of beta cells in the rapid phase was due to apoptosis, and was able to be prevented with a caspase inhibitor. 2. We intravitrealy injected drugs which are reported to prevent rodent RGC death after axotomy. Combination of BDNF, CNTF and forskolin facilitated survival of cat RGCs, especially beta cells. Nipradilol (NP), an anti-glaucoma drug, protects injured RGCs from death at 10^<-7> mol.3. Rates of prolongation of regenerated axons were estimated in cat RGCs. The average rate of whole RGCs was estimated as 1.1 mm/d. Alpha cells had the most rapid rate as 1.4 mm/d, compared with beta cells' (1.1 mm/d) and other cells' (1.0 mm/d). The highest rate of alpha cells reflects their greater ability to regenerate axons. The values are used as control values when a method to facilitate axonal elongation.4. Combination of BDNF, CNTF and forskolin increased numbers of regenerated RGCs, but did not increase axonal regeneration of cells which survived axotomy without axonal regeneration. NP at 10^<-7> mol increased numbers of regenerated RGCs into 3-4 fold, and shortened time for 20 mm axonal elongation by 7 days.

哺乳动物视网膜神经节细胞（RGCs）轴突再生成移植的周围神经段，但再生的RGCs数量平均为2%。它们太小，无法恢复受损视力的功能，也无法引导干细胞衍生的RGCs轴突进入中央视觉区域。因此，应该开发增加数量的方法。我们测试了几种药物来保护轴突切除的RGCs的死亡，因为轴突再生的首要条件是被切除的RGCs的存活。我们还得到了轴突再生率。为了研究提高RGC存活率的方法，我们检测了无性系切除RGC的生存曲线。β细胞在第3天至第7天迅速退化，而α细胞直到第14天缓慢退化。快速期β细胞的死亡是由于细胞凋亡，并且可以用caspase抑制剂阻止。2. 我们通过玻璃体内注射了一些药物，据报道这些药物可以防止啮齿类动物在肛切开术后死亡。BDNF、CNTF和forskolin的联合使用促进了猫RGCs的存活，尤其是β细胞。Nipradilol （NP）是一种抗青光眼药物，可保护受伤的RGCs免于10^<-7> mol的死亡。在cat RGCs中估计再生轴突的延长率。整个rgc的平均速率估计为1.1 mm/d。与β细胞（1.1 mm/d）和其他细胞（1.0 mm/d）相比，α细胞以1.4 mm/d的速度最快。α细胞的最高比率反映了它们更强的轴突再生能力。当一种方法促进轴突延长时，这些值用作控制值。BDNF、CNTF和forskolin联合使用可增加再生RGCs的数量，但不能增加未进行轴突再生的轴突切除后存活细胞的轴突再生。NP浓度为10^<-7> mol时，再生rgc数增加3-4倍，轴突延长20 mm的时间缩短7天。