Molecular mechanism of regeneration and plasticity of the injured central nervous system

2011 Fiscal Year Final Research Report

• Project/Area Number: 19679007
• Research Category: Grant-in-Aid for Young Scientists (S)
• Allocation Type: Single-year Grants
• Research Field: Cerebral neurosurgery
• Research Institution: Osaka University
• Principal Investigator: YAMASHITA Toshihide 大阪大学, 医学系・研究科, 教授 (10301269)
• Project Period (FY): 2007 – 2011
• Keywords: 機能脳神経外科学 / 再生

Research Abstract

In the adult mammalian central nervous system(CNS), it is well known that injured axons exhibit very limited regeneration ability. Due to this lack of appropriate axonal regeneration, a traumatic damage to the adult brain and spinal cord frequently causes permanent neuronal deficits such as paralysis. Several axon growth inhibitors in the CNS have been identified in the myelin. These proteins contribute to the lack of regeneration of the injured CNS. However, it is noted that spontaneous functional recovery sometimes occurs following CNS injury. Synaptic plasticity in pre-existing pathways and the formation of new circuits through collateral sprouting of lesioned and unlesioned fibers are important components of this spontaneous recovery process. Our research has focused on regeneration and plasticity of destructed neural network in the CNS. It unveiled the mechanism of plasticity of neural circuit after injury to the adult CNS, although it had been believed that adult CNS does not regenerate if damaged.

Research Products

• [Journal Article] RGMamodulates T cell responses and is involved in autoimmune encephalomyelitis (2011)
  • Author(s): Muramatsu, R., Kubo, T., Mori, M., Nakamura, Y., Fujita, Y., Aktsu, T., Okuno, T., Taniguchi, J., Kumanogoh, A., Yoshida, M., Mochizuki, H., Kuwabara, S. and Yamashita, T
  • Journal Title: Nature Medicine Volume: 17 Pages: 488-494
  • Peer Reviewed
• [Journal Article] Myelin suppresses axon regeneration by PIR-B/ SHP-mediated inhibition of Trkactivity (2011)
  • Author(s): Fujita, Y., Endo, S., Takai, T. and Yamashita, T
  • Journal Title: EMBO J Volume: 30 Pages: 1389-1401
  • Peer Reviewed
• [Journal Article] Rncr3, which encodes miR-124a, is required for hippocampal axon development and retinal cone photoreceptor survival through Lhx2 suppression (2011)
  • Author(s): Sanuki, R., Onishi, A., Koike, C., Muramatsu, R., Watanabe, S., Muranishi, Y, Irie, S., Ueno, S., Koyasu, T., Matsui, R., Cherasse, Y., Urade, Y., Watanabe, D., Kondo, M., Yamashita, T. and Furukawa, T
  • Journal Title: Nature Neurosci Volume: 14 Pages: 1125-1134
  • Peer Reviewed
• [Journal Article] FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons (2011)
  • Author(s): Yamagishi, S., Hampe1, F., Hata, K., del Toro, D., Schwark, M., Kvachnina, E., Bastmeyer, M., Yamashita, T., Tarabykin, V., Klein, R. and* Egea. J
  • Journal Title: EMBO J Volume: 30 Pages: 2920-2933
  • Peer Reviewed
• [Journal Article] Axonal remodeling for motor recovery after traumatic brain injury requires downregulation ofγ-aminobutyric acid signaling (2011)
  • Author(s): Lee, S., Ueno, M. and Yamashita, T
  • Journal Title: Cell Death Dis Volume: 2 Pages: e133
  • Peer Reviewed
• [Journal Article] The p75 receptor mediates axon growth inhibition through an association with PIR-B (2011)
  • Author(s): Fujita, Y., Takashima, R. Endo, S., Takai, T. and Yamashita, T
  • Journal Title: Cell Death Dis Volume: 2 Pages: e198
  • Peer Reviewed
• [Journal Article] Axotomy induces axonogenesis in hippocampal neurons through STAT3 (2011)
  • Author(s): Ohara, R., Fujita, Y., Hata, K., Nakagawa, M. and Yamashita, T
  • Journal Title: Cell Death Dis Volume: 2 Pages: e175
  • Peer Reviewed
• [Journal Article] Keratan sulfate restricts neural plasticity after spinal cord injury (2011)
  • Author(s): Imagama, S., Sakamoto, K., Tauchi, R., Shinjo, R., Ohgomori, T., Ito, Z., Zhang, H., Nishida, Y., Asami, N., Takeshita, S., Sugiura, N., Watanabe, H., Yamashita, T., Ishiguro, N., Matsuyama, Y. and Kadomatsu K
  • Journal Title: J. Neurosci Volume: 31 Pages: 17091-17102
  • Peer Reviewed
• [Journal Article] Paired immunoglobulin-like receptor B knockout does not enhance axonal regeneration or locomotor recovery after spinal cord injury (2011)
  • Author(s): Nakamura, Y., Fujita, Y., Ueno, M., Takai, T. and Yamashita, T
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 1876-1883
  • Peer Reviewed
• [Journal Article] Neogenin : Areceptor for bone morphogenetic proteins (2011)
  • Author(s): Hagihara, M., Endo, M., Hata, K., Higuchi, C., Takaoka, K., Yoshikawa, H. and Yamashita, T
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 5157-5165
  • Peer Reviewed
• [Journal Article] Genetic deletion of paired immunoglobulin-like receptor B does not promote axonal plasticity or functional recovery after traumatic brain injury (2010)
  • Author(s): Omoto, S., Ueno, M., Mochio, S., Takai, T. and Yamashita, T
  • Journal Title: J. Neurosci Volume: 30 Pages: 13045-13052
  • Peer Reviewed
• [Journal Article] N-acetylglucosamine 6-O-sulfotransferase-1-deficient mice show better functional recovery after spinal cord injury (2010)
  • Author(s): Ito, Z., Sakamoto, K., Imagama, S., Matsuyama, Y., Zhang, H, Hirano, K., Ando, K., Yamashita, T., Ishiguro, N. and Kadomatsu, K
  • Journal Title: J. Neurosci Volume: 30 Pages: 5937-5947
  • Peer Reviewed
• [Journal Article] Reduction ofbrain Aβby Fluvastatin, an HMG-CoA reductase inhibitor, through increase in degradation of APP-CTFs and Aβclearance (2010)
  • Author(s): Shinohara, M., Sato, N., Kurinami, H., Takeuchi, D., Takeda, S., Shimamura, M., Yamashita, T., Uchiyama, Y., Rakugi, H. and Morishita, R
  • Journal Title: J. Biol. Chem Volume: 285 Pages: 22091-22102
  • Peer Reviewed
• [Journal Article] Unc5B associates with LARG to mediate the action of repulsive guidance molecule (2009)
  • Author(s): Hata, K., Kaibuchi, K., Inagaki, S. and Yamashita, T
  • Journal Title: J. Cell Biol Volume: 184 Pages: 737-750
  • Peer Reviewed
• [Journal Article] CIDP sera inhibit axonal growth of mouse DRG neurons by activation of Rho-kinase (2009)
  • Author(s): Taniguchi, J., Sawai, S., Mori, M., Kubo, T., Kanai, K., Misawa, S., Isose, S., Yamashita, T. and Kuwabara, S
  • Journal Title: Ann. Neurol Volume: 66 Pages: 694-697
  • Peer Reviewed
• [Journal Article] Inactivation of Ras by p120GAP via FAK dephosphorylation mediates RGMa-induced growth cone collapse (2009)
  • Author(s): Endo, M. and Yamashita, T
  • Journal Title: J. Neurosci Volume: 29 Pages: 6649-6662
  • Peer Reviewed
• [Journal Article] Engulfment of axon debris by microglia requires p38 MAPK activity (2009)
  • Author(s): Tanaka, T., Ueno, M. and Yamashita, T
  • Journal Title: J. Biol. Chem Volume: 284 Pages: 21626-21636
  • Peer Reviewed
• [Journal Article] Rap1 is involved in the signal transduction of myelin-associated glycoprotein (2008)
  • Author(s): Taniguchi, J., Fujitani, M., Endo, M., Kubo, T., Fujitani, M., Miller, F. D., Kaplan, D. R. and Yamashita, T
  • Journal Title: Cell Death Differ Volume: 15 Pages: 408-419
  • Peer Reviewed
• [Journal Article] Neogenin regulates neuronal survival through DAP-kinase (2008)
  • Author(s): Fujita, Y., Taniguchi, J., Uchikawa, M., Endo, M., Hata, K., Kubo, T., Mueller, B. K. and Yamashita, T
  • Journal Title: Cell Death Differ Volume: 15 Pages: 1593-1608
  • Peer Reviewed
• [Journal Article] Regulation of axonal elongation and pathfinding from the entorhinal cortex to the dentate gyrus in the hippocampus by the chemokine stromal cell-derived factor 1α (2008)
  • Author(s): Ohshima, Y., Kubo, T., Koyama, R., Ueno, M., Nakagawa, M. and Yamashita, T
  • Journal Title: J. Neurosci Volume: 28 Pages: 8344-8353
  • Peer Reviewed
• [Journal Article] Role of RhoA in Activity-Dependent Cortical Axon Branching (2008)
  • Author(s): Ohnami, S., Endo, M., Hirai, S., Uesaka, N., Hatanaka, Y., Yamashita, T. and Yamamoto, N
  • Journal Title: J. Neurosci Volume: 28 Pages: 9117-9121
  • Peer Reviewed
• [Journal Article] Inhibition of eIF2B∂/ F11A3. 2 during adulthood extends lifespan in Caenorhabditis elegans (2008)
  • Author(s): Tohyama, D., Yamaguchi, A., and Yamashita, T
  • Journal Title: FASEB J Volume: 22 Pages: 4327-4337
  • Peer Reviewed
• [Presentation] 中枢神経疾患と免疫制御 (2012)
  • Author(s): 山下俊英
  • Organizer: 大阪大学蛋白研セミナー「神経疾患の克服に向けて」
  • Place of Presentation: 大阪
  • Year and Date: 20120301-02
• [Presentation] 脳・脊髄障害後の神経回路修復を制御するメカニズム (2012)
  • Author(s): 山下俊英
  • Organizer: 第8回宮崎サイエンスキャンプ
  • Place of Presentation: 宮崎
  • Year and Date: 20120218-19
• [Presentation] 視神経の軸索再生阻害の分子機構とその制御による再生誘導 (2011)
  • Author(s): 山下俊英
  • Organizer: 第22回日本緑内障学会総会
  • Place of Presentation: 秋田
  • Year and Date: 20110923-25
• [Presentation] 脳・脊髄はなぜ再生できないのか? (2011)
  • Author(s): 山下俊英
  • Organizer: 第29回大阪科学賞受賞記念講演
  • Place of Presentation: 大阪
  • Year and Date: 2011-11-02
• [Presentation] Cell signaling cascades regulating restoration of neuronal network following injury to the central nervous system (2010)
  • Author(s): 山下俊英
  • Organizer: BMB2010(第33回日本分子生物学会・第83回日本生化学会合同大会)
  • Place of Presentation: 神戸
  • Year and Date: 20101207-10
• [Presentation] 脳・脊髄損傷後の神経回路修復のメカニズム (2010)
  • Author(s): 山下俊英
  • Organizer: Neuro2010
  • Place of Presentation: 神戸
  • Year and Date: 20100902-04
• [Presentation] 脳・脊髄損傷後の神経回路修復を制御する分子とそのシグナル伝達機構 (2010)
  • Author(s): 山下俊英
  • Organizer: 名古屋大学グローバルCOE系統講義ニューロサイエンスコース
  • Place of Presentation: 名古屋
  • Year and Date: 2010-12-02
• [Presentation] 脳・脊髄損傷後の神経回路修復のメカニズム (2010)
  • Author(s): 山下俊英
  • Organizer: 第1回Stroke Science Academy特別講演
  • Place of Presentation: 福岡
  • Year and Date: 2010-06-18
• [Presentation] 中枢神経損傷後の機能回復と神経回路の修復 (2010)
  • Author(s): 山下俊英
  • Organizer: 第540回北里医学会招待学術講演会
  • Place of Presentation: 神奈川
  • Year and Date: 2010-04-12
• [Presentation] 中枢神経回路の修復と再生 (2009)
  • Author(s): 山下俊英
  • Organizer: 第62回日本自律神経学会総会教育講演
  • Place of Presentation: 和歌山
  • Year and Date: 20091105-06
• [Presentation] 中枢神経損傷後の機能回復と神経回路の修復機構 (2009)
  • Author(s): 山下俊英
  • Organizer: 大阪大学蛋白研セミナー「神経回路の形成と修復を司る分子機構」
  • Place of Presentation: 大阪
  • Year and Date: 20091029-30
• [Presentation] 中枢神経損傷後の機能回復と神経回路の修復 (2009)
  • Author(s): 山下俊英
  • Organizer: 第13回日本神経麻酔・集中治療研究会特別講演
  • Place of Presentation: 大阪
  • Year and Date: 20090327-28
• [Presentation] 脊髄損傷後の機能回復と神経回路の修復機構 (2009)
  • Author(s): 山下俊英
  • Organizer: 第19回神経科学の基礎と臨床
  • Place of Presentation: 大阪
  • Year and Date: 2009-12-19
• [Presentation] 中枢神経損傷後の機能回復と神経回路の修復 (2009)
  • Author(s): 山下俊英
  • Organizer: 第8回Cutting Edge Forum
  • Place of Presentation: 大阪
  • Year and Date: 2009-11-28
• [Presentation] Convergent signaling regulating axon regeneration after CNS injuries (2008)
  • Author(s): 山下俊英
  • Organizer: BMB2008(第31回日本分子生物学会・第81回日本生化学会合同大会)
  • Place of Presentation: 神戸
  • Year and Date: 20081209-12
• [Presentation] 脳損傷後に神経回路はいかにして修復されるか (2008)
  • Author(s): 山下俊英
  • Organizer: 第51回日本神経化学会大会
  • Place of Presentation: 富山
  • Year and Date: 20080911-13
• [Presentation] 脳神経回路の修復治療法の展望 (2008)
  • Author(s): 山下俊英
  • Organizer: 第18回脳血管シンポジウム特別講演
  • Place of Presentation: 大阪
  • Year and Date: 2008-09-06
• [Presentation] 中枢神経回路の修復機構と再生に向けた戦略 (2008)
  • Author(s): 山下俊英
  • Organizer: 第11回オフタルモニューロプロテクション研究会特別講演
  • Place of Presentation: 東京
  • Year and Date: 2008-07-26
• [Presentation] 脳・脊髄はなぜ再生しないのかー再生阻害の分子機構と創薬への応用- (2008)
  • Author(s): 山下俊英
  • Organizer: 世界脳週間2008大阪講演会
  • Place of Presentation: 大阪
  • Year and Date: 2008-06-15
• [Presentation] 脳・脊髄はなぜ再生しないのか (2008)
  • Author(s): 山下俊英
  • Organizer: 第21回日本脳死・脳蘇生学会総会・学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2008-05-09
• [Presentation] 中枢神経系の軸索再生を制御する分子機構 (2008)
  • Author(s): 山下俊英
  • Organizer: 第85回日本生理学会大会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-26
• [Presentation] 中枢神経損傷後の機能回復と神経回路の修復機構 (2008)
  • Author(s): 山下俊英
  • Organizer: 第7回日本再生医療学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-03-14
• [Presentation] 損傷中枢神経回路の再生とRhoキナーゼ (2008)
  • Author(s): 山下俊英
  • Organizer: 第9回脳血管疾患治療研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-01
• [Book] Repulsive guidance molecule(RGM)-自己免疫性脊髄炎・多発性硬化症の新たな治療標的、リウマチ科 (2012)
  • Author(s): 山下俊英
• [Book] 視神経の軸索再生阻害の分子機構とその制御による再生誘導、Frontiers in Graucoma (2012)
  • Author(s): 山下俊英
  • Total Pages: 64-65
• [Book] 中枢神経の軸索再生を制御する分子機構、脳21 (2011)
  • Author(s): 山下俊英
  • Total Pages: 108-113
• [Book] 中枢神経障害による神経症状を改善する治療薬の開発の現状と今後、医薬品医療機器レギュラトリーサイエンス (2011)
  • Author(s): 山下俊英
  • Total Pages: 858-862
• [Book] 中枢神経回路の修復と再生、自律神経 (2010)
  • Author(s): 山下俊英
  • Total Pages: 80-81
• [Book] 軸索伸展阻害因子と中枢神経の再生、分子脳血管病 (2009)
  • Author(s): 山下俊英
  • Total Pages: 45-50
• [Book] 脊髄の軸索再生を制御する分子群、臨床整形外科 (2009)
  • Author(s): 山下俊英
  • Total Pages: 378-380
• [Book] 中枢神経回路の再編、日本薬理学会誌 (2009)
  • Author(s): 村松里衣子、山下俊英
  • Total Pages: 46-47
• [Book] 中枢神経回路の修復機構、脳21 (2009)
  • Author(s): 山下俊英
  • Total Pages: 306-311
• [Book] 中枢神経回路の修復機構-そのポテンシャル、脳21 (2009)
  • Author(s): 山下俊英
  • Total Pages: 279-282
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/molneu/index.html
• [Patent(Industrial Property Rights)] 神経成長促進剤 (2010)
  • Inventor(s): 山下俊英、藤田幸
  • Industrial Property Rights Holder: 国立大学法人大阪大学
  • Industrial Property Number: 特許、特願2010-41180
  • Filing Date: 2010-02-26