Role of HGF in the nervous system

HGF 在神经系统中的作用

• 批准号: 18500294
• 负责人: FUNAKOSHI Hiroshi
• 金额: $ 2.63万
• 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: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18500294/
• 关键词: HGF; c-Met; Nervous System; Neurotrophic; Neurodegenerative disease; Regenerative Medicine; transgenic; ALS; 肝細胞増殖因子(HGF); 脳虚血; オリゴデンドロサイト; トランスジェニックマウス

(1) The role of HGF in amyotrophic lateral sclerosis and its gliosis : We have previously reported that overexpression of HGF in the nervous system can attenuate spinal motor neuron death, motor fiber degeneration, improve motor function and prolongs the life span of a transgenic mouse model of ALS. We here demonstrated that HGF has the ability to attenuate degeneration of not only spinal but also brain stem motor neurons, such as hypoglossal and facial motor neurons. In addition, we have demonstrated that HGF could attenuate gliosis (astrocytosis and micangliosis) in ALS model mice. Furthermore, intrathecal delivery of recombinant human HGF protein could attenuate the progression the disease in a transgenic rat model of ALS in a dose-dependent manner. It should be noted that HGF could show beneficial effect even when it is delivered from the onset of the disease. These findings raise the possibility that HGF could be used as a therapeutic agent for ALS and related disorders.(2) The ro … More le of HGF in oligodendrocyte development : In contrast to the role f HGF in neurons, the role of HGF in oligodendrocyte development is poorly understood. Since knockout mice of HGF and its receptor c-Met are embryonic lethal, we took advantage to use stereotaxic administration of recombinant HGF protein and its functional blocking antibody into the brain at P7 and P10 to show the role of HGF in oligodendrocyte precursor cells (OPCs) and found that HGF accelerates proliferation of OPCs while inhibits differentiation into oligodendrocytes, which express inhibitory molecules for neurite outgrowth. Taken together with the notion that HGF promotes neurite outgrowth and the level of HGF is high during the neurite outgrowth while low in the periods of mediation, HGF may play an important role in coordination of neurite out growth ad oligodendrocyte development.(3) The role of HGF-like protein in primary microglia: We have provided the first evidence that HGF-like protein (HLP) / macrophage stimulating protein (MSP), only the structural relative of HGF, has the ability to promote microglial migration and regulate production of cytokines, such as IL-6,GM-CSF and ions. Less

(1)HGF在肌萎缩性脊髓侧索硬化症及其神经胶质增生中的作用：我们之前报道，神经系统中HGF的过度表达可以减轻脊髓运动神经元死亡、运动纤维变性，改善运动功能并延长ALS转基因小鼠模型的寿命。我们在此证明，HGF 不仅能够减轻脊髓变性，还能减轻脑干运动神经元（例如舌下运动神经元和面部运动神经元）的变性。此外，我们还证明 HGF 可以减弱 ALS 模型小鼠的神经胶质细胞增生（星形细胞增多症和微胶质细胞增多症）。此外，重组人 HGF 蛋白的鞘内递送可以以剂量依赖的方式减弱 ALS 转基因大鼠模型中疾病的进展。应该指出的是，即使在疾病发作时施用 HGF 也可以显示出有益的作用。这些发现提出了HGF可用作ALS和相关疾病的治疗剂的可能性。(2) HGF在少突胶质细胞发育中的作用：与HGF在神经元中的作用相反，HGF在少突胶质细胞发育中的作用知之甚少。由于HGF及其受体c-Met基因敲除小鼠具有胚胎致死性，因此我们利用重组HGF蛋白及其功能阻断抗体在P7和P10时脑部立体定向给药来展示HGF在少突胶质细胞前体细胞（OPC）中的作用，发现HGF加速OPC的增殖，同时抑制其分化为少突胶质细胞。 少突胶质细胞，表达神经突生长的抑制分子。结合HGF促进神经突生长以及神经突生长期间HGF水平较高而介导期间HGF水平较低的观点，HGF可能在协调神经突生长和少突胶质细胞发育中发挥重要作用。（3）HGF样蛋白在原代小胶质细胞中的作用：我们提供了第一个证据表明HGF样蛋白（HLP）/ 巨噬细胞刺激蛋白（MSP）是HGF的结构相关蛋白，具有促进小胶质细胞迁移和调节IL-6、GM-CSF和离子等细胞因子产生的能力。较少的

项目成果

神経変性疾患のサイエンスThe Fronders in Medical Sciences (高橋良輔 編)南山堂

《医学科学前沿》（高桥凉介主编） Nanzando

• 发表时间: 2007
• 作者: 船越 洋;ほか.
• 通讯作者: ほか.

Intrathecal delivery of hepatocyte growth factor from amyotrophic lateral sclerosis onset suppresses disease progression in rat amyotrophic lateral sclerosis model

• DOI: 10.1097/nen.0b013e318159886b
• 发表时间: 2007-11-01
• 期刊: JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
• 影响因子: 3.2
• 作者: Ishigaki, Aya;Aoki, Masashi;Itoyama, Yasuto
• 通讯作者: Itoyama, Yasuto

Induction of hepatocyte growth factor by fucoidan and fucoidan-derived oligosaccharides

岩藻依聚糖和岩藻依聚糖衍生寡糖诱导肝细胞生长因子

• 发表时间: 2008
• 期刊: J. Pharm. Pharmacol 60
• 作者: Fukuta;K.;et. al.
• 通讯作者: et. al.

神経変性疾患のサイエンス The Frontiers in Medical Sciences(高橋良輔 編)南山堂

神经退行性疾病科学 医学前沿（高桥亮介主编） Nanzando

• 发表时间: 2007
• 作者: 船越 洋;ほか.
• 通讯作者: ほか.

HGFの神経保護作用機序

HGF的神经保护机制

• 发表时间: 2007
• 期刊: Clinical Neuroscience 25巻・6号(In press)
• 作者: Hoshino M.;Qi M. L.;Yoshimura N.;Miyashita T.;Tagawa K.;Wada Y. I.;Enokido Y.;Marubuchi S.;Harjes P.;Arai N.;Oyanagi K.;Blandino G.;Sudol M.;Rich T.;Kanazawa I.;Wanker E. E.;Saitoe M.;Okazawa H;船越 洋 他
• 通讯作者: 船越 洋 他