| Project/Area Number |
15GS0319
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| Research Category |
Grant-in-Aid for Creative Scientific Research
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| Allocation Type | Single-year Grants |
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| Research Institution | Nagoya University |
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Principal Investigator |
KAIBUCHI Kozo Nagoya University, Graduate School of Medicine, Professor (00169377)
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| Co-Investigator(Kenkyū-buntansha) |
USUKURA Jiro Nagoya University, Center for Cooperative Research in Advanced Science&Technology, Professor (30143415)
KURODA Shinya University of Tokyo, Graduate School of Science, Professor (50273850)
AMANO Mutsuki Nagoya University, Graduate School of Medicine, Associate Professor (90304170)
TAYA Shinichiro Nagoya University, Graduate School of Medicine, Associate Professor (60362232)
ARIMURA Nariko Tamagawa University, Brain Science Institute, COE Associate Professor (20420375)
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| Project Period (FY) |
2003 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥317,980,000 (Direct Cost: ¥244,600,000、Indirect Cost: ¥73,380,000)
Fiscal Year 2007: ¥78,000,000 (Direct Cost: ¥60,000,000、Indirect Cost: ¥18,000,000)
Fiscal Year 2006: ¥78,000,000 (Direct Cost: ¥60,000,000、Indirect Cost: ¥18,000,000)
Fiscal Year 2005: ¥78,000,000 (Direct Cost: ¥60,000,000、Indirect Cost: ¥18,000,000)
Fiscal Year 2004: ¥83,980,000 (Direct Cost: ¥64,600,000、Indirect Cost: ¥19,380,000)
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| Keywords | polarily / axon / migration / CRMP-2 / Rho family / signal transduction / simulation / contraction / 細胞極性 / 遊走 / Rho / Rac / Par-3 / 軸索 / ミオシン / IQGAP / Disc1 / Kinesin / コンピューターシミュレーション / Sra-1 / WAVE1 / チューブリン / アクチン / エンドサイトーシス / 運命決定 / 神経細胞 / PAR複合体 / PI3-kinase / GSK-3β / IQGAP1 / APC / PAR-3 / KIF3A / Numb |
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| Research Abstract |
Cell polarization is an essential step for cellular functions, but the underlying mechanisms to establish and maintain cell polarity are not fully understood. We tried to clarify the signal transduction mechanisms controlling cell polarization by the use of cell migration and neuronal axon/dendrite determination as model systems.
1. Identification of extracellular signals modulating neuronal polarity and following signaling pathways.
Extracellular signals such as laminin induced the production of PIP3, inactivation of GSK-3β, and resultant activation of CRMP-2. Active CRMP-2 bound to tubulin, Sra-1, and Numb, and regulated tubulin polymerization, actin remodeling, and L1 endocytosis at growth cone, which contributed to the axon elongation and neuronal axon/dendrite determination. In addition, Par complex composed of Par-3, Pare and aPKC modulated the Rac activity through Rac GEF (Tiam1/Tiam2) to establish neuronal polarity and front-rear polarity of migrating cells.
2. Analysis of signali
… More
ng pathways underlying cell migration
During establishment and maintenance of front-rear polarity in cell migration, Rac/IAGAP1 regulated dynamics of both actin and microtubules through APC/CLIP-170. Rho/Rho-kinase inhibited Par complex formation and adjusted the Rac activity properly both at the front and rear.
3. Role of molecular and vesicular traffic in cell polarization and migration
CRMP-2 interacted with tubulin, Sra-1 and Slp1/TrkB, and transported them to the tip of axon as a “cargo receptor". Numb regulated integrin endocytosis at the front of migrating cell, which is supposed to be necessary for directional migration.
4. Analysis of signal networks by computer simulation
The computational model for endothelial cell contraction (activation of myosin) suggested the existence of unidentified pathway for sustained cell contraction in silico, and the novel pathway mediated by iPLA2 was identified in vivo. The computational model for establishment of front-rear polarity of migrating cells by Rho family GTPases was developed. Less
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