Study on molecular biological mechanism of regeneration of olfactory receptor neurons and regeneration medicine of olfaction

• Project/Area Number: 18390458
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: Kobe University
• Principal Investigator: NIBU Ken-ichi Kobe University, 大学院医学研究科, 教授 (20251283)
• Co-Investigator(Kenkyū-buntansha): TERASHIMA Toshio 神戸大学, 大学院医学研究科, 教授 (20101892) ; DOI Kiyoshi 神戸大学, 医学部附属病院, 助教 (00379380) ; 森 憲作 東京大学, 医学系研究科, 教授 (60008563)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,020,000 (Direct Cost: ¥15,200,000、Indirect Cost: ¥2,820,000); Fiscal Year 2008: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2007: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2006: ¥5,800,000 (Direct Cost: ¥5,800,000)
• Keywords: 嗅覚 / 嗅神経 / 嗅上皮 / 再生 / 骨髄間質幹細胞 / bFGF / DNA マイクロアレイ / 嗅神経細胞 / 嗅球 / RNA / DNAマイクロアレイ / NRG

Research Abstract

嗅神経細胞の障害による嗅覚障害の新たな治療法開発を目指して、嗅神経細胞の再生における分子機構の解明を進めるとともに、様々な再生医療の可能性を検討した。分子機構解明の研究では、DNA マイクロアレイを用いて、嗅上皮の再生過程における遺伝子発現を解析。新規遺伝子Fezf1 が嗅上皮内での嗅神経細胞の配列に重要であることを示した。治療法についての研究では、アデノウイルスベクターが嗅神経細胞のみならず、嗅球への遺伝子産物導入にも有効であることを示し、Cre/loxP システムを用いて、Bcl2 遺伝子の導入により、嗅神経細胞のアポトーシスを抑制できることを示した。更に、bFGF の鼻腔内局所投与により、嗅神経細胞の前駆細胞である球状基底細胞の増殖をみること、骨髄間質幹細胞を鼻腔内に直接投与することにより、嗅上皮内に移植することができることを示した。

Research Products

• [Journal Article] Fezf1 is required for penetration of the basal lamina by olfactory axons to promote olfactory development (2009)
  • Author(s): Watanabe Y, Inoue K, Yamamoto A, Nakai N, Nakatani J, Nibu K, Sato N, Iiboshi Y, Yusa K, Kondoh G, Takeda J,Terashima T,Takumi T.
  • Journal Title: J Comp Neuro 2009 515 Pages: 565-584
  • Peer Reviewed
• [Journal Article] The distribution and severity of spontaneous lesions in neuroepithelium and Bowman45-49, 2008's glands in mouse olfactory mucosa: age-related progression. (2009)
  • Author(s): Kondo K, Watanabe K, Sakamoto T, Suzukawa K, Nibu K, Kaga K, Yamasoba T.
  • Journal Title: Cell Tissue Res 2009 335 Pages: 489-503
  • Peer Reviewed
• [Journal Article] 嗅覚の加齢とアンチエイジング (2008)
  • Author(s): 丹生健一
  • Journal Title: Ant-Aging Medicine 4 Pages: 625-628
  • Peer Reviewed
• [Journal Article] 感覚器の再生医療 嗅覚の再生医療-嗅上皮の再生に向けて (2008)
  • Author(s): 丹生健一 土井清司 西川 匡 越智尚樹
  • Journal Title: 医学のあゆみ226 Pages: 991-995
  • Peer Reviewed
• [Journal Article] 嗅覚研究の進歩-嗅神経細胞の再生医療- (2008)
  • Author(s): 丹生健一
  • Journal Title: 日本耳鼻咽喉科学会会報 111 Pages: 45-49
  • Peer Reviewed
• [Journal Article] 鼻副鼻腔の組織修復 (2008)
  • Author(s): 黒野祐一 丹生健一
  • Journal Title: 日本鼻科学会会誌 47 Pages: 59-60
  • Peer Reviewed
• [Journal Article] 嗅覚器の解剖学 (2007)
  • Author(s): 土井清司
  • Journal Title: 神経内科 66 Pages: 317-321
  • Peer Reviewed
• [Journal Article] 呼吸性嗅覚障害 (2007)
  • Author(s): 土井清司 丹生健一
  • Journal Title: ENT/er 3 Pages: 6-6
  • Peer Reviewed
• [Journal Article] 嗅上皮の発生・再生 (2007)
  • Author(s): 土井清司 丹生健一
  • Journal Title: JOHNS 23 Pages: 693-697
  • Peer Reviewed
• [Journal Article] The expression of neuN in the development of olfactory bulb and epithelium of mice (2007)
  • Author(s): Wei H, Li X, Yu G, Cao Z, Nibu K
  • Journal Title: Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 21 Pages: 363-365
  • Peer Reviewed
• [Journal Article] Age-related changes in cell density and proliferation rate of olfactory ensheathing cells in lamina propria of postnatal mouse olfactory mucosa. (2006)
  • Author(s): Watanabe K, Kondo K, Takeuchi N,Nibu K, Kaga K.
  • Journal Title: Brain Res. 2006 1116 Pages: 82-92
  • Peer Reviewed
• [Journal Article] Bcl-2 expression mediated by Cre/loxP system in olfactory epithelium. (2006)
  • Author(s): Doi K, Nibu K, Okado H, Terashima T.
  • Journal Title: Neurosci Lett. 2006 339 Pages: 67-70
  • NAID: 120000942529
  • Peer Reviewed
• [Journal Article] unctional MRI を用いたニオイの研究 (2006)
  • Author(s): 堅田敬太 丹生健一
  • Journal Title: 頭頸部自律神経 20 Pages: 55-56
  • Peer Reviewed
• [Journal Article] Bc1-2 expression mediated by Cre/loxP system in olfactory epithelium. (2006)
  • Author(s): Doi K, Nibu K, Okado H, Terashima.
  • Journal Title: Neurosci Lett. 339 Pages: 67-70
• [Journal Article] Age-related changes in cell density and proliferation rate of olfactory ensheathing cells in lamina propria of postnatal mouse olfactory mucosa. (2006)
  • Author(s): Watanabe K, Kondo K, Takeuchi N, Nibu K, Kaga K.
  • Journal Title: Brain Res 1116 Pages: 82-92
• [Journal Article] Effect on olfactory epithelium of intranasal administration of basic fibroblast growth factor.
  • Author(s): Nishikawa T, Doi K, Ochi N, Katsunuma S,Nibu K.
  • Journal Title: Neuroreport 20 Pages: 764-769
  • Peer Reviewed
• [Journal Article] Functional MRI of regional brain responses to"pleasant" and "unpleasant" odors
  • Author(s): Keita K, Sakai N, Doi K, Kawamitsu H,Fujii M, Sugimura K, Nibu K.
  • Journal Title: Acta Otolaryngologica in press Pages: 0-0
  • Peer Reviewed
• [Journal Article] Fezfl is required for penetration of the basal laminaby olfactory axons to promote olfactory development
  • Author(s): Watanabe Y, Inoue K, Yamamoto A, Nakai N, Nakatani J, Nibu K, Sato N, Iiboshi Y, Yusa K, Kondoh G, Takeda J, Terashima T, Takumi T.
  • Journal Title: J Comp Neurol (掲載確定) (in press)
  • Peer Reviewed
• [Journal Article] Effect on olfactory epithelium of intranasal administration of basic fibrobiast growth factor.
  • Author(s): Nishikawa T, Doi K, Ochi N, Katsunuma S, Nibu K.
  • Journal Title: Neuroreport (掲載確定) (in press)
  • Peer Reviewed
• [Journal Article] Functional MRI of regional brain responses to “pleasant" and “unpleasant" odors
  • Author(s): Keita K, Sakai N, Doi K, Kawamitsu H, Fujii M, Sugimura K, Nibu K.
  • Journal Title: Acta otolaryngologica (掲載確定) (in press)
  • Peer Reviewed
• [Presentation] 骨髄間質幹細胞移植による嗅神経細胞の再生 (2008)
  • Author(s): 越智尚樹 西川 匡 土井清司 丹生健一
  • Organizer: 第109回日本耳鼻咽喉科学会総会・学術講演会
  • Place of Presentation: 大阪
  • Year and Date: 2008-05-15
• [Presentation] Effect of bFGF on olfactory epithelium. (2007)
  • Author(s): Nishikawa T, Nibu K, Ochi N.
  • Organizer: 12th congress of the International Rhinologic Society.
  • Place of Presentation: Italy.
  • Year and Date: 2007-12-05
• [Presentation] Local Injection of Bone Marrow Derived Stem Cells into Nasal Cavity Is Useful for Regeneration of Olfactory Receptor Neurons. (2007)
  • Author(s): Ochi N, Nibu K, Doi K, Nishikawa T.
  • Organizer: 12th congress of the International Rhinologic Society.
  • Place of Presentation: Italy.
  • Year and Date: 2007-12-05
• [Presentation] ヒト繊維芽細胞蔵相因子(bFGF)点鼻によるマウス嗅上皮の変化に関する免疫組織学的検討 (2007)
  • Author(s): 西川 匡、丹生健一、土井清司、越智尚樹
  • Organizer: 第46回日本鼻科学会総会・学術講演会
  • Place of Presentation: 宇都宮
  • Year and Date: 2007-09-27
• [Presentation] 骨髄間質幹細胞移植による嗅神経細胞の再生 (2007)
  • Author(s): 越智尚樹 西川 匡 土井清司 丹生健一
  • Organizer: 第46回日本鼻科学会総会・学術講演会
  • Place of Presentation: 宇都宮
  • Year and Date: 2007-09-27
• [Presentation] 加齢に伴うマウス嗅上皮の変性の進行 (2007)
  • Author(s): 近藤健二 渡辺健太 丹生健一 山岨達也
  • Organizer: 第108回日本耳鼻咽喉科学会総会・学術講演会
  • Place of Presentation: 金沢
  • Year and Date: 2007-05-17
• [Presentation] シンポジウム 嗅覚研究・臨床の進歩 嗅神経細胞の再生 (2007)
  • Author(s): 丹生健一
  • Organizer: 第108回日本耳鼻咽喉科学会総会・学術講演会
  • Place of Presentation: 20070517
  • Year and Date: 2007-05-17
• [Presentation] 2種類のにおい刺激に対するにおい中枢の反応 (2006)
  • Author(s): 堅田敬太 坂井信之 丹生健一
  • Organizer: 第45回日本鼻科学会
  • Place of Presentation: 四日市
  • Year and Date: 2006-09-21
• [Presentation] Bcl-2 epressoin mediated by Cre/loxP system in olfactory epithelium. (2006)
  • Author(s): Doi K, Nibu K.
  • Organizer: 25th International Sympoium on Infection and Allergy of the Nose.
  • Place of Presentation: Tampere, Finland
  • Year and Date: 2006-06-21
• [Presentation] Functional magnetic resonance imaging study of human olfaction. (2006)
  • Author(s): Katada K. Nibu K.
  • Organizer: 25th International Sympoium on Infectionand Allergy of the Nose.
  • Place of Presentation: Tampere, Finland
  • Year and Date: 2006-06-21