Promotion of researches for protective regeneration of injured neurons

促进损伤神经元保护性再生研究

• 批准号: 13307001
• 负责人: KIYAMA Hiroshi
• 金额: $ 34.11万
• 依托单位: Osaka City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13307001/
• 关键词: nerve injury; neuronal regeneration; differential display; adeno virus; transcription factor; neurite elongation; Akt; CRMP; 移植・再生医療; 解剖学; 再生医学; 脳・神経; 脳神経疾患; 糖蛋白

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.

这项研究的重点是广泛的神经再生领域中的保护性再生。研究了三个主要主题：（1）与神经元再生相关的分子的鉴定，（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）治疗，尝试使用基因转移技术实验动物。本研究新发现AIGP、ADAMTS-1、CRMP-2等与神经元再生过程相关。此外，我们还成功将 ATF3 确定为主要的神经损伤相关转录因子。几乎所有轴突受损的神经元中都观察到 ATF3 表达。 ATF3 表达对神经损伤的功能影响之一是 ATF3 与 cJun 一起加速 Hsp27 等基因表达，从而激活最强的生存因子 Akt 之一。接下来，我们尝试将本研究中作为神经再生相关基因衍生的基因转移到大鼠受损的神经元中。例如，通过使用腺病毒实现了 CRMP 在神经损伤的运动神经元中的过度表达。这种 CRMP 表达加速了神经突伸长的速度。这些腺病毒介导的体内基因表达系统可能是神经元保护和神经再生的有效治疗方法。在这项研究中，我们还揭示了体外和体内 DINE 表达的主要转录因子是 STAT3 和 ATF3/cJun 异二聚体。本项目获得的结果为神经再生研究提供了有用的工具，在实验动物中检查某种分子的功能，也为脑外伤、缺血、脊髓等临床疾病的治疗干预提供了可能性。受伤等

项目成果

Honma M, et al.: "Developmental alteration of nerve injury induced glial cell line-derived neurotrophic factor (GDNF) receptor expression is crucial for the determination of injured motoneuron fate"J Neurochem.. 82. 961-976 (2002)

Honma M 等人：“神经损伤诱导的神经胶质细胞源性神经营养因子 (GDNF) 受体表达的发育改变对于确定受损运动神经元的命运至关重要”J Neurochem.. 82. 961-976 (2002)

Iida N, et al.: "Requirement of Ras for the activation of mitogen-activated protein (MAP) kinase by calcium influx, cAMP and neurotrophin in hippocampal neurons"J.Neurosci.. 21(17). 6549-6466 (2001)

Iida N 等人：“海马神经元中钙流入、cAMP 和神经营养素激活丝裂原激活蛋白 (MAP) 激酶所需的 Ras”J.Neurosci.. 21(17)。

Takamiya A, et al.: "Inflammation induces serine protease inhibitor 3 (SPI-3) expression in the rat pineal gland"Neuroscience.. 113(2). 387-394 (2002)

Takamiya A 等人：“炎症诱导大鼠松果体中丝氨酸蛋白酶抑制剂 3 (SPI-3) 的表达”Neuroscience.. 113(2)。

Taira E, Tsukamoto Y, Kohama K, Maeda M, Kiyama H, Miki N: "Expression and involvement, of gicerin, a cell adhesion molecule, in the development of chick optic tectum"J Neurochem. 88(4). 891-899 (2004)

Taira E、Tsukamoto Y、Kohama K、Maeda M、Kiyama H、Miki N：“细胞粘附分子甘油在鸡视顶盖发育中的表达和参与”J Neurochem。

Iida N: "Requirement of Ras for the activation of mitogen-activated protein (MAP) kinase by calcium influx, cAMP and neurotrophin in hippocampal neurons"J. Neurosci. 21(17). 6459-6466 (2001)

Iida N：“海马神经元中钙流入、cAMP 和神经营养素激活丝裂原激活蛋白 (MAP) 激酶所需的 Ras”J。