Establishment of delivery system to the brain for antilsodies, enzymes, and neurotrophic factors without breakage of blood-brain barrier

建立不破坏血脑屏障的抗抗体、酶和神经营养因子向大脑的输送系统

• 批准号: 16300121
• 负责人: SAWADA Makoto
• 金额: $ 8.74万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16300121/
• 关键词: microglia; brain-targeting molecule; chemical conjugates; brain-targeting tag

It is known that a certain kind of cells can migrate into a specific target organ from blood flow when injected. They include brain-migrating cells such as neural stem cells, a part of bone marrow derived cells, lymphocytes and microglia. Microglia are subpopulation of glial cell in the brain and play important roles in the development, differentiation and maintenance of neural cells via their phagocytic activity and production of enzymes, cytokines and trophic factors. The mechanism of microglial brain migration is thought to be via a trans cellular pathway because microglial migration occur with out any breakage of the blood brain barrier. I found that microglia clone cells retain the capability to migrate into the brain from the circulation and that microglia can deliver the gene of interest to brain, by injecting microglia transfected galactosidase gene expressing vector to the circulation.Meanwhile, I have successfully isolated several peptide which can mimic and/or compete the microglial brain-migrating activity. The peptides are small enough to be attached to several chemicals and biochemical materials and also to put in the sequence franking to recombinant protein as a brain-migrating tag. I indicated the ability of the peptides to penetrate through the BBB and distribute in brain parenchyma, therefore, the modified peptides are useful for the multi-purpose delivery tool to the brain, an availability of which was proved by several analyses including in vivo PET imaging.Now I and my colleagues are trying to produce several brain-targeting drugs with our novel peptide. Our peptides may open the way of delivering into brain parenchyma even a compound as the PET-ligand with poor penetrability into brain. Further, we expect that our peptides offer the more flexibility in use for the delivery of many bio active materials into the brain.

已知，当注射时，某种细胞可以从血流中迁移到特定的靶器官。它们包括脑迁移细胞，如神经干细胞、一部分骨髓来源细胞、淋巴细胞和小胶质细胞。小胶质细胞是脑内神经胶质细胞的亚群，通过其吞噬活性和产生酶、细胞因子和营养因子，在神经细胞的发育、分化和维持中发挥重要作用。小胶质细胞迁移的机制被认为是通过跨细胞途径进行的，因为小胶质细胞迁移发生时没有任何血脑屏障的破坏。通过将小胶质细胞转基因的半乳糖苷酶基因表达载体注入循环中，我发现小胶质细胞克隆细胞保持了从循环向脑内迁移的能力，并且小胶质细胞可以将感兴趣的基因输送到脑内。同时，我成功地分离出了几个能够模拟和/或竞争小胶质细胞脑迁移活性的多肽。这些多肽足够小，可以附着在几种化学物质和生化材料上，也可以放入序列中，作为大脑迁移的标签与重组蛋白打交道。我指出了这些多肽能够穿透血脑屏障并分布在脑实质中，因此，修饰后的多肽是一种有用的多功能脑部给药工具，包括体内PET成像在内的多项分析证明了这种工具的有效性。现在，我和我的同事们正试图用我们的新型多肽来制造几种脑靶向药物。我们的多肽可能会打开进入脑实质的途径，甚至可能是一种渗透性很差的化合物作为PET-配体进入大脑。此外，我们预计我们的多肽在将许多生物活性物质输送到大脑中时提供了更大的灵活性。

项目成果

Activation of voltage-gated proton channels during lactic acidosis in microglia, pH-sensing cells in the CNS.

小胶质细胞（中枢神经系统中的 pH 敏感细胞）乳酸性酸中毒期间电压门控质子通道的激活。

• 发表时间: 2006
• 期刊: Neurosci. Res. 55
• 作者: Kuno;M. et al.
• 通讯作者: M. et al.

Role of cytokines in inflammatory process in Parkinson's disease.

• DOI: 10.1007/978-3-211-45295-0_57
• 发表时间: 2006
• 期刊: Journal of neural transmission. Supplementum
• 作者: M. Sawada;K. Imamura;T. Nagatsu;T. Nagatsu

Cellular and Molecular Mechanisms of Parkinson's Disease : Neurotoxins, Causative Genens, and Inflammatory Cytokines

帕金森病的细胞和分子机制：神经毒素、致病基因和炎症细胞因子

• 发表时间: 2006
• 期刊: Cellular and Molecular Neurobiology 26(4-6)
• 作者: NAGATSU;T;SAWADA;M
• 通讯作者: M

Amyloid-beta peptides induce cell proliferation and macrophage colony-stimulating factor expression via the PI3-kinase/Akt pathway in cultured Ra2 microgllial cells.

β 淀粉样肽通过培养的 Ra2 小胶质细胞中的 PI3 激酶/Akt 途径诱导细胞增殖和巨噬细胞集落刺激因子表达。

• 发表时间: 2005
• 期刊: FEBS Letters 579
• 作者: ADACHI;K;Yimin;Yu;SATAKE;K;MATSUYAMA;Y;ISHIGURO;N;SAWADA;M;HIRATA;Y;KIUCHI;K;HAGIHARA Hideo;KANEKO Yoko S;HIMEDA Toshiki;MORIYA Masayuki;NAKAMICHI Kazuo;NAKAMICHI Kazuo;ITO Sachiko
• 通讯作者: ITO Sachiko

Evaluation of toxic conversion of microglia on rat striatum injury model using animal PET

动物PET评价小胶质细胞对大鼠纹状体损伤模型的毒性转化

• 发表时间: 2007
• 作者: SUZUKI;H;TOYAMA;H;HATANO;K;KUDO;G;ITO;F;ONO;K;KATO;T;ITO;K;SAWADA;M
• 通讯作者: M