Enhancement of Neurogenesis by Progenitor Cells as a Target for Gene Therapy in Cerebral Ischemia

祖细胞增强神经发生作为脑缺血基因治疗的靶点

• 批准号: 13670643
• 负责人: KITAGAWA Kazuo
• 金额: $ 2.18万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670643/
• 关键词: Cerebral ischemia; Neurogenesis; Neural Progenitor; Cyclooxygensase; Prostaglandin; Hippocampus; Neuron; 神経幹細胞; 脳卒中

We evaluated proliferation of neural progenitors and neurogenesis in the subgranular zone (SGZ) of hippocampal dentate and subventricular zone (SVZ) in transient forebrain and focal ischemia. The number of proliferating cells in the SGZ reached a peek a week after ischemia, and proliferating cells represented the neuronal phenotype 4 weeks after bromodeoxyuridine labeling. The number of proliferating cells in the SVZ also increased after focal cerebral ischemia. However, differential expression of selective markers for neural stem/progenitor cells, Musashil(Msil) and nestin, was observed in both regions. Both Msil and nestin were impressed in neural progenitors in SVZ, however, only Msil was observed in progenitors in SGZ. Thereafter, we examined the involvement of cyclooxygenase-2 (COX2) on induced proliferation of neural progenitors after ischemia by using COX-2 selective inhibitor, NS398, and COX-2 knockout mice. Because induction of COX-2 protein was observed in neuron and astrocytes, but not in neural progenitors, prostaglandin may be involved in increased neurogenesis after ischemia. Our results demonstrated that proliferation of neural progenitors and neurogenesis after ischemia can be modified by modulation of COX-2. COX-2 may be a potential target of gene therapy for enhancing neurogenesis

我们观察了短暂性前脑和局灶性脑缺血大鼠海马齿状回颗粒下带(SGZ)和脑室下带(SVZ)神经前体细胞的增殖和神经发生。缺血后1周，SGZ内的增殖细胞数量达到高峰，4周后，增殖细胞呈现神经元表型。局灶性脑缺血后SVZ内的增殖细胞数量也增加。然而，神经干/祖细胞的选择性标记物Musashil(MSIL)和Nestin在这两个区域的表达存在差异。MSIL和Nestin在SVZ的神经前体细胞中均有表达，而在SGZ的神经前体细胞中仅有MSIL表达。此后，我们利用COX-2选择性抑制剂NS398和COX-2基因敲除小鼠，研究了COX2在脑缺血后诱导神经前体细胞增殖中的作用。由于在神经元和星形胶质细胞中观察到COX-2蛋白的诱导，而在神经前体细胞中未观察到COX-2蛋白的诱导，前列腺素可能参与了缺血后神经再生的增加。我们的结果表明，缺血后神经前体细胞的增殖和神经再生可以通过COX-2的调节而改变。COX-2可能是促进神经发生的基因治疗的潜在靶点

项目成果

Yoshiki Yagita, Kazuo Kitagawa, Tsutomu Sasaki, Takaki Miyata, Hideyuki Okano, Masatsugu Hori, Masayasu Matsumoto: "Differential expression of musashil and nestin in the adult rat hippocampus after ischemia"Journal of Neuroscience Research. 69. 750-756 (2

Yoshiki Yagita、Kazuo Kitakawa、Tsutomu Sasaki、Takaki Miyata、Hideyuki Okano、Masatsugu Hori、Masayasu Matsumoto：“缺血后成年大鼠海马中 musashil 和 nestin 的差异表达”神经科学研究杂志。

北川一夫, 松本昌泰他: "The protective effect of apolipaptotein E agaist ischemic neuronal injury is nediated through antioxidant action"Journal of Neuroscience Research. (印刷中).

Kazuo Kitakawa、Masayasu Matsumoto 等人：“载脂蛋白 E 对缺血性神经元损伤的保护作用是通过抗氧化作用介导的”《神经科学研究杂志》（出版中）。

八木田佳樹, 北川一夫他: "Neurogenesis by Progenitor Cells in the Ischemic Adult Rat Hippocampus"Stroke. 32. 1890-1896 (2001)

Yoshiki Yagita、Kazuo Kitakawa 等人：“缺血性成年大鼠海马中祖细胞的神经发生”32. 1890-1896 (2001)

Takasawa K, Kitagawa K, et al.: "Increased Prdiferation of Neural Progenitor Cells but Reduced Survival of Newborn Cells in the Contralateral Hippocampus after Focal Cerebral Isohemia"Journal of Cerebral Blood Flow & Metabolism. 22. 299-307 (2002)

高泽 K、北川 K 等人：“局灶性脑缺血后对侧海马神经祖细胞增殖增加，但新生细胞存活率降低”Journal of Cerebral Blood Flow

高沢健一郎, 北川一夫他: "Increased proliferation of neural progenitor cells but reduced survival of newborn cells in the contralateral hippocampus after focal cerebral ischemia in rats"Journal of Cerebral Blood Flow and Metabolism. 22. 299-307 (2002)

Kenichiro Takazawa、Kazuo Kitakawa 等人：“大鼠局灶性脑缺血后，神经祖细胞增殖增加，但对侧海马新生细胞存活率降低”《脑血流与代谢杂志》22. 299-307 (2002)。