HGF family that includes HGF & HLP/MSP as a novel neurotrophic family

HGF 家族，包括 HGF

• 批准号: 14580742
• 负责人: FUNAKOSHI Hiroshi
• 金额: $ 2.62万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580742/
• 关键词: Neurodegenerative disease; HGF; c-Met; Neurotrophic; Amyotrophic lateral sclerosis (ALS); Neurons; Glia; Transgenic mice; 肝細胞増殖因子(HGF); HGF-like protein(HLP); Ron; ミクログリア; 神経栄養因子

We previously indeitified that HGF and its family member, HGF-like protein (HLP)/MSP are novel neurotrophic factors for variety of neurons, such as cerebral cortex, hippocampus, midbrain dopaminergic, sensory, motor and sympathetic neurons. In the current study, we further investigated the roles of HGF and HLP in the nervous system, especially in neurodegenerative diseases. In addition, by generation and analyses of LIMK-2 KO mice, we found that LIM-kinase 2 play an important role in neuronal degenerative process.(1) Roles of HGF in amyotrophic lateral sclerosis (ALS): Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motoneurons and degeneration of motor axons. We showed that overexpression of hepatocyte growth factor (HGF) in the nervous system attenuates motoneuron death and axonal degeneration and prolongs the life span of transgenic mice overexpressing mutated SOD1. HGF prevented induction of caspase-1 in motoneurons an … More d retained the levels of the glial-specific glutamate transporter (EAAT2/GLT1) in reactive astrocytes. We propose that HGF may be the first example of an endogenous growth factor that can alleviate the symptoms of ALS by direct neurotrophic activities on motoneurons and indirect activities on glial cells, presumably favoring a reduction in glutamatergic neurotoxicity.(2) Roles of HLP/MSP in the nervous system: We previously reported that HLP act as a novel neurotrophic factor for chicken sensory neurons. Here we identified that Ron/HLP receptor is expressed in primary microglia and HLP accelerates microglial activities in vitro. Taken together with notion that HLP is neurotrophic, HLP may be one of the critical factor involving not only the protecting process of the neurodegeneration but also the degeneration and regeneration processes of the nervous system.(3) Roles of LIMKase-2 (LIMK2) in the nervous system: By generation and analyses if LIMK2 deficient mice, we found that limk2 variants were differently expressed in hippocampal neurons and play important roles in neurodegenerative process of hippocampal neurons. Less

HGF及其家族成员HGF样蛋白(HLP)/MSP是一种新的神经营养因子，可作用于大脑皮层、海马区、中脑多巴胺能、感觉、运动神经元和交感神经元等多种神经元。在目前的研究中，我们进一步研究了HGF和HLP在神经系统中的作用，特别是在神经退行性疾病中的作用。此外，通过对LIMK-2 KO小鼠的产生和分析，我们发现LIM-K2在神经元退变过程中起着重要的作用。(1)HGF在肌萎缩侧索硬化症(ALS)中的作用：肌萎缩侧索硬化症(ALS)是一种以运动神经元进行性丧失和运动轴突变性为特征的致死性神经退行性疾病。我们发现，在神经系统中过表达肝细胞生长因子(HGF)可以减轻运动神经元死亡和轴突变性，并延长过表达突变SOD1的转基因小鼠的寿命。肝细胞生长因子抑制…运动神经元半胱氨酸天冬氨酸蛋白酶-1的诱导更多的d保留了反应性星形胶质细胞中胶质细胞特异性谷氨酸转运体(EAAT2/GLT1)的水平。我们认为HGF可能是第一个内源性生长因子，通过对运动神经元的直接神经营养活性和对神经胶质细胞的间接活性来减轻ALS的症状，可能有利于减少谷氨酸能神经毒性。(2)HLP/MSP在神经系统中的作用：我们先前报道HLP是一种新的鸡感觉神经元神经营养因子。在此，我们证实RON/HLP受体在原代小胶质细胞中表达，并且HLP在体外可以促进小胶质细胞的活动。结合HLP具有神经营养作用的观点，HLP可能不仅参与了神经退行性变的保护过程，而且还参与了神经系统的退变和再生过程。(3)LIMK2在神经系统中的作用：通过对LIMK2缺陷小鼠的生成和分析，我们发现LIMK2变体在海马神经元中有不同的表达，并在海马神经元的神经退化过程中发挥重要作用。较少

项目成果

Kishi YA, Funakoshi H, et al.: "Molecular cloning, expression and partial characterization of Xksy, Xen opus member of the Sky family of receptor tyrosine kinases."Gene. 288(1-2). 29-40 (2002)

Kishi YA、Funakoshi H 等人：“受体酪氨酸激酶 Sky 家族 Xen opus 成员 Xksy 的分子克隆、表达和部分表征。”基因。

K.Oshima, T.Nakamura, et al.: "Intrathecal injection of HVJ-E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats."FASEB J.. 18(1). 212-214 (2003)

K.Oshima、T.Nakamura等人：“将含有HGF基因的HVJ-E鞘内注射到脑脊液中可以预防和改善大鼠的听力损伤。”FASEB J.. 18(1)。

船越 洋, 中村 敏一: "神経栄養因子による神経難病治療の可能性"現代医療. 34(1). 245-259 (2003)

Hiroshi Funakoshi、Toshikazu Nakamura：“使用神经营养因子治疗顽固性神经疾病的可能性”现代医学 34(1) 245-259 (2003)。

船越 洋, 中村 敏一: "神経栄養因子による神経難病治療の可能性"現代医療. 34(1). 245-259 (2002)

Hiroshi Funakoshi、Toshikazu Nakamura：“使用神经营养因子治疗顽固性神经疾病的可能性”现代医学 34(1) 245-259 (2002)。

Funakoshi H, Yonemasu T, Nakano T, et al.: "Identification of Gas6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons"J. Neurosci Res.. 68(2). 150-160 (2002)

Funakoshi H、Yonemasu T、Nakano T 等人：“Gas6（Sky 和 ​​Axl 受体酪氨酸激酶的推定配体）的鉴定，作为海马神经元的新型神经营养因子”J.