Promotion of researches for protective regeneration of injured neurons

在广泛的神经再生领域中，本研究的重点是保护性再生。主要研究了三个方面：(1)与神经元再生相关分子的鉴定；(2)利用腺病毒载体鉴定各种神经元再生相关分子的功能后果；(3)在实验动物中使用基因转移技术进行治疗性尝试。本研究新发现AIGP、ADAMTS-1、CRMP-2等与神经元再生过程相关。此外，我们已经成功地建立了ATF3作为一个主要的神经损伤相关转录因子。ATF3在几乎所有轴突受损的神经元中均有表达。ATF3表达在神经损伤反应中的功能后果之一是，ATF3与cJun一起加速了Hsp27等基因的表达，而Hsp27可以激活最强的生存因子之一Akt。接下来，我们试图将本研究中获得的神经再生相关基因转移到大鼠损伤神经元中。例如，利用腺病毒在神经损伤的运动神经元中实现了CRMP的过表达。CRMP的表达加快了神经突伸长的速度。这些腺病毒介导的基因在体内表达系统可能是一种有效的治疗神经元保护和神经再生的方法。在本研究中，我们还发现体外和体内DINE表达的主要转录因子是STAT3和ATF3/cJun异源二聚体。本项目的研究结果为神经再生研究提供了有用的工具，在实验动物中检测某种分子的功能，也为脑外伤、缺血、脊髓损伤等临床疾病的治疗干预开辟了可能性。

This study was focused on Protective Regeneration amongst wide range of neural regeneration field. Three major topics were investigated: (1)Identification of molecules, which are associated with neuronal regeneration, (2)Identification of functional consequences of various neuronal regeneration associated molecules by using adenovirus vector, (3)A therapeutic, attempts using gene transfer technique in experimental animals. In this study we have newly identified that AIGP, ADAMTS-1,CRMP-2 and etc are associated with neuronal regeneration process. In addition, we have succeeded in establishing ATF3 as a major nerve injury associated transcription factor. ATF3 expression is observed in almost all neurons whose axons are damaged. One of the functional consequences of ATF3 expression in response to nerve injury, is that ATF3 together with cJun accelerates gene expressions such as Hsp27, which activates one of the strongest survival factor Akt. Next we have attempted to transfer genes, which are derived in this study as nerve regeneration associated genes, into injured neurons of rat. For instance over expression of CRMP in nerve-injured motor neurons was achieved by using adenovirus. This CRMP expression accelerated the speed of neurite elongation. These adenovirus mediated gene expression system in vivo may be a potent therapeutic approach for the neuron protection and nerve regeneration. In this study we have also revealed that the major transcription factor for DINE expression was STAT3 and ATF3/cJun heterodimer both in vitro and in vivo. The results obtained in the present project provide useful tool for the nerve regeneration studies, in which the function of a certain molecule are examined in experimental animal, and also open up a possibility of therapeutic intervention in clinical conditions like brain trauma, ischemia, spinal cord injury, and etc.