Development of a new regenerative treatment for Parkinson's disease by way of inducing proliferation, migration, and differentiation of neural stem cells in situ

通过原位诱导神经干细胞增殖、迁移和分化，开发帕金森病的新再生疗法

• 批准号: 19300132
• 负责人: SAKAGUCHI Kazushige
• 金额: $ 11.9万
• 依托单位: Wakayama Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2007
• 资助国家: 日本
• 起止时间: 2007 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19300132/
• 关键词: エフリン; パーキンソン病; 神経幹細胞; ラット; 再生医学; Eph; ephrin; 再生医療; マーモセット; ephrin(エフリン)

Adult mouse brain has two neurogenic areas that contain neural stem/progenitor cells (NSPC). They can differentiate to nerve cells, astrocytes, and oligodendrocytes. Recent studies demonstrated that neural stem cells in the subventricular zone send extensions to the lateral ventricle and receive signals. Parkinson's disease, a neurodegenerative disorder, can be treated by supplying dopamine to improve symptoms, but this cannot be a curative treatment. Sooner or later, the dopaminergic neurons degenerate and become incapable of produce dopamine, resulting in deterioration of symptoms. Fetal nigral tissue transplantation can be one of the candidates of curative treatment, but is not regarded as a standard method due to ethical problems and difficulty in obtaining enough amount of such tissue. ES cells and iPS cells can be differentiated to dopaminergic cells, but the extent of differentiation and occasional occurrence of tumors must be controlled before applying to human. Immuno-rejectiv … More e reactions and ethical problems must be controlled. Degeneration of neurons in the nigrostriatal tract deplete striatal dopamine and causes Parkinson's disease. Striatum is located close to the lateral ventricle, suggesting that the subventricular neural stem cells are the good candidates for the treatment of this disease by causing proliferation, migration and differentiation. In the current project, we examined whether Eph/ephrin signaling system can be used to induce these phenomenon for the treatment of Parkinson's disease in rats and marmosettes. In rats, injection of clustered ephrin-A1 into the lateral ventricle could induce NSPC proliferation, migration and differentiation to dopaminergic neurons, and angiogenesis in the striatum. These effects resulted in behavioral improvement of rats with hemilateral nigrostriatal lesion. The histological and behavioral improvement lasted at least for 12 weeks. Marmosettes have so small a ventricle that it was difficult to inject clustered ephrin-A1 into the lateral ventricle. However, multiple injection of ephrin-A1 in and around the lateral ventricle improved the animal behavior as measured by Supermex. Recombinant ephrin-A1 fused with the coiled-coil domain of cartilage oligomeric matrix protein was produced in E. coli, but the product was not soluble and precipitated in water, probably due to formation of large multimers. Because of these results, we used the authentic method of clustering ephrin-A1-Fc by anti-IgG(Fc) antibody. Less

成年小鼠脑内有两个含有神经干/祖细胞（NSPC）的神经原性区域。它们可以分化为神经细胞、星形胶质细胞和少突胶质细胞。最近的研究表明，脑室下区的神经干细胞向侧脑室发送延伸并接收信号。帕金森病是一种神经退行性疾病，可以通过提供多巴胺来改善症状来治疗，但这不是一种治愈性治疗。多巴胺能神经元迟早会退化，无法产生多巴胺，导致症状恶化。胎儿黑质组织移植可以是治愈性治疗的候选者之一，但由于伦理问题和难以获得足够量的这种组织而不被视为标准方法。ES细胞和iPS细胞可以分化为多巴胺能细胞，但在应用于人类之前必须控制分化的程度和偶尔发生的肿瘤。免疫排斥 ...更多信息 必须控制反应和伦理问题。黑质纹状体束神经元的退化会耗尽纹状体多巴胺，导致帕金森病。纹状体位于侧脑室附近，表明室管膜下神经干细胞是通过引起增殖、迁移和分化来治疗这种疾病的良好候选者。在本项目中，我们研究了Eph/ephrin信号系统是否可以用于诱导这些现象，用于治疗大鼠和猕猴的帕金森病。在大鼠，注射成簇的ephrin-A1到侧脑室可以诱导NSPC增殖，迁移和分化为多巴胺能神经元，并在纹状体血管生成。这些作用导致单侧黑质纹状体损伤大鼠的行为改善。组织学和行为学改善至少持续12周。旱獭的脑室很小，很难将成簇的ephrin-A1注入侧脑室。然而，在侧脑室内和周围多次注射ephrin-A1改善了动物的行为，如通过Superpermex测量的。将软骨寡聚基质蛋白的卷曲螺旋结构域与ephrin-A1融合，在大肠杆菌中表达。大肠杆菌，但该产品是不溶的，并沉淀在水中，可能是由于形成大的多聚体。由于这些结果，我们使用了通过抗IgG（Fc）抗体聚类ephrin-A1-Fc的可靠方法。少

项目成果

Involvement of GCMB in the transcriptional regulation of the human parathyroid hormone gene in a parathyroid-derived cell line, PT-r : Effects of calcium and 1,25(OH)2D3.

GCMB 参与甲状旁腺衍生细胞系 PT-r 中人甲状旁腺激素基因的转录调节：钙和 1,25(OH)2D3 的影响。

• 发表时间: 2010
• 期刊: Bone 47
• 作者: Masayuki Kawahara;Yasumasa Iwasaki;Kazushige Sakaguchi;Takafumi Taguchi;Mitsuru Nishiyama;Takeshi Nigawara;Machiko Kambayashi;Takahiro Sawada;Xuefeng Jing;Masayasu Miyajima;Yoshio Terada;Kozo Hashimoto;Toshihoro Suda
• 通讯作者: Toshihoro Suda

新規成長ホルモン不応性成長障害の発症機序

新型生长激素难治性生长障碍的发病机制

• 发表时间: 2009
• 作者: 宮嶋正康;京雪楓;澤田貴宏;島田栄美;飯田啓二;村垣泰光;千原和夫;坂口和成
• 通讯作者: 坂口和成

Dwarfism caused by a defect in a novel growth hormone signaling pathway.

侏儒症是由一种新型生长激素信号通路缺陷引起的。

• 发表时间: 2008
• 作者: Masayasu Miyajima;Xuefeng Jing;Takahiro Sawada;Keiji Iida;Yasuteru Muragaki;Emi Shimada;Kazuo Chihara;Kazushige Sakaguchi
• 通讯作者: Kazushige Sakaguchi

Regulation of ephexin1, a guanine nucleotide exchange factor of Rho family GTPases, by fibroblast growth factor receptor-mediated tyrosine phosphorylation

• DOI: 10.1074/jbc.m704430200
• 发表时间: 2007-10-19
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Zhang, Yueqiang;Sawada, Takahiro;Sakaguchi, Kazushige
• 通讯作者: Sakaguchi, Kazushige

中枢神経障害治療剤および中枢神経障害の治療方法

中枢神经障碍的治疗剂及中枢神经障碍的治疗方法

• 发表时间: 2008