Functional Regeneration of Inner Ear Hair Cells

• Project/Area Number: 15591809
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: KYOTO UNIVERSITY
• Principal Investigator: FUJINO Kiyohiro KYOTO UNIVERSITY, Graduate School of medicine, Assistant Professor, 医学研究科, 助手 (50359832)
• Co-Investigator(Kenkyū-buntansha): NAKAGAWA Takayuki KYOTO UNIVERSITY, Graduate School of medicine, Assistant Professor, 医学研究科, 助手 (50335270) ; TSUJI Jun KYOTO UNIVERSITY, Graduate School of medicine, Lecturer, 医学研究科, 講師 (30252448) ; KITA Tomoko KYOTO UNIVERSITY, Graduate School of medicine, Researcher, 医学研究科, 研究員(科学技術振興) (20362519)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 2003: ¥2,900,000 (Direct Cost: ¥2,900,000)
• Keywords: Notch signaling / RBP-J / Cre-loxP / Wnt signaling / GSK-3β / hair cells / 神経幹細胞 / 器官培養 / 細胞移植

Research Abstract

1.Knockout of RBP-J
Notch signaling is the important signal transduction pathway for cell proliferation and differentiation. Inhibition of this system enables the unusual cell proliferation that lead to the regeneration of hair cell. Using adenovirus vector and Cre-loxP system in the culture preparation of organ of Corti, we knocked out the gene of RBP-J : a transcription factor of Notch signaling. We achieved the ectopic generation of hair cells.
2.Pharmacological inhibition of RBP-J
In the culture preparation of organ of Corti, RBP-J was blocked by γ-secretase. Similarly to the genetic inhibition of RBP-J, ectopic hair cells were generated.
3.Knockout of GSK-3β
Wnt signaling is the important signal transduction pathway for cell proliferation. Activating Wnt signaling enable abnormal cell proliferation. We knocked out GSK-3β ; a inhibiting factor of Wnt signaling with the similar method to the RBP-J. We found the ectpic hair cell growth.
4.Pharmacological inhibition of GSK-3β
In the culture preparation of organ of Corti, GSK-3β was blocked by several drugs. Similarly to the genetic inhibition of RBP-J, ectopic hair cells were generated.

Research Products

• [Journal Article] Elevation of superoxide dismutase increases acoustic trauma from noise exposure. (2005)
  • Author(s): Endo T, Nakagawa T, Iguchi F, Kita T, Okano T, Sha SH, Schacht J, Shiga A, Kim TS, Ito J
  • Journal Title: Free Radic Biol Med 38 Pages: 492-498
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Serofendic acid promotes survival of auditory hair cells and neurons of mice. (2005)
  • Author(s): Kita T, Nakagawa T, Kim TS, Iwai K, Takebayashi S, Akaike A, Ito J.
  • Journal Title: Neuroreport 16 Pages: 689-692
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cell therapy for inner ear diseases. (2005)
  • Author(s): Nakagawa T, Ito J.
  • Journal Title: Curr Pharm Des 11 Pages: 1203-1207
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Aging effects on vestibulo-ocular responses in C57BL/6 mice : comparison with alteration in auditory function. (2005)
  • Author(s): Shiga A, Nakagawa T, Nakayama M, Endo T, Iguchi F, Kim TS, Naito Y, Ito J.
  • Journal Title: Audiol Neurootol 10 Pages: 97-104
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Nuclear translocation of beta-catenin in developing auditory epithelia of mice. (2005)
  • Author(s): Takebayashi S, Nakagawa T, KoJima K, Kim TS, Endo T, Iguchi F, Kita T, Yamamoto N, Ito J.
  • Journal Title: Neuroreport 16 Pages: 431-434
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Elevation of superoxide dismutase increases acoustic trauma from noise exposure. (2005)
  • Author(s): Endo T, Nakagawa T, Iguchi F, Kita T, Okano T, Sha SH, Schacht J, Shiga A, Kim TS, Ito J.
  • Journal Title: Free Radic Biol Med 38 Pages: 492-498
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nuclear translocation of beta-catenin in developing auditory epithelia of mice. (2005)
  • Author(s): Takebayashi S, Nakagawa T, Kojima K, Kim TS, Endo T, Iguchi F, Kita T, Yamamoto N, Ito J.
  • Journal Title: Neuroreport 16 Pages: 431-434
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Application of cell therapy to inner ear diseases (2004)
  • Author(s): Nakagawa T, Ito J.
  • Journal Title: Acta Otolaryngol Suppl 551 Pages: 6-9
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Nestin expression in the developing rat cochlea sensory epithelia. (2004)
  • Author(s): KoJima K, Takebayashi S, Nakagawa T, Iwai K, Ito J.
  • Journal Title: Acta Otolaryngol Suppl 551 Pages: 14-17
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of beta-catenin in developing auditory epithelia of mice. (2004)
  • Author(s): Takebayashi S, Nakagawa T, KoJima K, Kim TS, Kita T, Dong Y, Endo T, Iguchi F, Naito Y, Omori K, Ito J.
  • Journal Title: Acta Otolaryngol Suppl 551 Pages: 18-21
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Induction of cell proliferation and beta-catenin expression in rat utricles in vitro. (2004)
  • Author(s): Kim TS, Nakagawa T, Lee JE, FuJino K, Iguchi F, Endo T, Naito Y, Omori K, Lefebvre PP, Ito J.
  • Journal Title: Acta Otolaryngol Suppl 551 Pages: 22-25
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Transplantation of neural stem cells into explants of rat inner ear. (2004)
  • Author(s): FuJino K, Kim TS, Nishida AT, Nakagawa T, Omori K, Naito Y, Ito J.
  • Journal Title: Acta Otolaryngol Suppl 551 Pages: 31-33
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of calretinin by fetal otocyst cells after transplantation into damaged rat utricle explants. (2004)
  • Author(s): Kim TS, KoJima K, Nishida AT, Tashiro K, Lee JE, FuJino K, Nakagawa T, Naito Y, Omori K, Lefebvre P, Ito J.
  • Journal Title: Acta Otolaryngol Suppl 551 Pages: 34-38
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Surgical techniques for cell transplantation into the mouse cochlea (2004)
  • Author(s): Iguchi F, Nakagawa T, Tateya I, Endo T, Kim TS, Dong Y, Kita T, KoJima K, Naito Y, Omori K, Ito J.
  • Journal Title: Acta Otolaryngol Suppl 551 Pages: 43-47
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Fates of mouse embryonic stem cells transplanted into the inner ears of adult mice and embryonic chickens. (2004)
  • Author(s): Sakamoto T, Nakagawa T, Endo T, Kim TS, Iguchi F, Naito Y, Sasai Y, Ito J.
  • Journal Title: Acta Otolaryngol Suppl 551 Pages: 48-52
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Transplantation of neural stem cells into the modiolus of mouse cochleae injured by cisplatin. (2004)
  • Author(s): Tamura T, Nakagawa T, Iguchi F, Tateya I, Endo T, Kim TS, Dong Y, Kita T, KoJima K, Naito Y, Omori K, Ito J.
  • Journal Title: Acta Otolaryngol Suppl 551 Pages: 65-68
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Signaling pathway for apoptosis of vestibular hair cells of mice due to aminoglycosides. (2004)
  • Author(s): Lee JE, Nakagawa T, Kim TS, Iguchi F, Endo T, Kita T, Murai N, Naito Y, Lee SH, Ito J.
  • Journal Title: Acta Otolaryngol Suppl 551 Pages: 69-74
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Radixin deficiency causes deafness associated with progressive degeneration of cochlear stereocilia. (2004)
  • Author(s): KitaJiri S, Fukumoto K, Hata M, Sasaki H, Katsuno T, Nakagawa T, Ito J, Tsukita S.
  • Journal Title: J Cell Biol 166 Pages: 559-570
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Role of reactive radicals in degeneration of the auditory system of mice following cisplatin treatment. (2004)
  • Author(s): Lee JE, Nakagawa T, Kim TS, Endo T, Shiga A, Iguchi F, Lee SH, Ito J
  • Journal Title: Acta Otolaryngol 124 Pages: 1131-1135
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Transplantation of bone marrow stromal cells into the cochlea of chinchillas. (2004)
  • Author(s): Naito Y, Nakamura T, Nakagawa T, Iguchi F, Endo T, FuJino K, Kim TS, Hiratsuka Y, Tamura T, Kanemaru S, Shimizu Y, Ito J.
  • Journal Title: Neuroreport 15 Pages: 1-4
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Application of cell therapy to inner ear diseases. (2004)
  • Author(s): Nakagawa T, Ito J.
  • Journal Title: Acta Otolaryngol Suppl Pages: 6-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nestin expression in the developing rat cochlea sensory epithelia. (2004)
  • Author(s): Kojima K, Takebayashi S, Nakagawa T, Iwai K, Ito J.
  • Journal Title: Acta Otolaryngol Suppl Pages: 14-17
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of beta-catenin in developing auditory epithelia of mice. (2004)
  • Author(s): Takebayashi S, Nakagawa T, Kojima K, Kim TS, Kita T, Dong Y, Endo T, Iguchi F, Naito Y, Omori K, Ito J.
  • Journal Title: Acta Otolaryngol Suppl Pages: 18-21
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Induction of cell proliferation and beta-catenin expression in rat utricles in vitro. (2004)
  • Author(s): Kim TS, Nakagawa T, Lee JE, Fujino K, Iguchi F, Endo T, Naito Y, Omori K, Lefebvre PP, Ito J.
  • Journal Title: Acta Otolaryngol Suppl Pages: 22-25
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Transplantation of neural stem cells into explants of rat inner ear. (2004)
  • Author(s): Fujino K, Kim TS, Nishida AT, Nakagawa T, Omori K, Naito Y, Ito J.
  • Journal Title: Acta Otolaryngol Suppl Pages: 31-33
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of calretinin by fetal otocyst cells after transplantation into damaged rat utricle explants. (2004)
  • Author(s): Kim TS, Kojima K, Nishida AT, Tashiro K, Lee JE, Fujino K, Nakagawa T, Naito Y, Omori K, Lefebvre P, Ito J.
  • Journal Title: Acta Otolaryngol Suppl Pages: 34-38
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Surgical techniques for cell transplantation into the mouse cochlea. (2004)
  • Author(s): Iguchi F, Nakagawa T, Tateya I, Endo T, Kim TS, Dong Y, Kita T, Kojima K, Naito Y, Omori K, Ito J.
  • Journal Title: Acta Otolaryngol Suppl Pages: 43-47
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fates of mouse embryonic stem cells transplanted into the inner ears of adult mice and embryonic chickens. (2004)
  • Author(s): Sakamoto T, Nakagawa T, Endo T, Kim TS, Iguchi F, Naito Y, Sasai Y, Ito J.
  • Journal Title: Acta Otolaryngol Suppl Pages: 48-52
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Transplantation of neural stem cells into the modiolus of mouse cochleae injured by cisplatin. (2004)
  • Author(s): Tamura T, Nakagawa T, Iguchi F, Tateya I, Endo T, Kim TS, Dong Y, Kita T, Kojima K, Naito Y, Omori K, Ito J.
  • Journal Title: Acta Otolaryngol Suppl Pages: 65-68
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Signaling pathway for apoptosis of vestibular hair cells of mice due to aminoglycosides. (2004)
  • Author(s): Lee JE, Nakagawa T, Kim TS, Iguchi F, Endo T, Kita T, Murai N, Naito Y, Lee SH, Ito J.
  • Journal Title: Acta Otolaryngol Suppl Pages: 69-74
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Radixin deficiency causes deafness associated with progressive degeneration of cochlear stereocilia. (2004)
  • Author(s): Kitajiri S, Fukumoto K, Hata M, Sasaki H, Katsuno T, Nakagawa T, Ito J, Tsukita S.
  • Journal Title: J Cell Biol 166 Pages: 559-570
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of reactive radicals in degeneration of the auditory system of mice following cisplatin treatment. (2004)
  • Author(s): Lee JE, Nakagawa T, Kim TS, Endo T, Shiga A, Iguchi F, Lee SH, Ito J.
  • Journal Title: Acta Otolaryngol 124 Pages: 1131-1135
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Transplantation of bone marrow stromal cells into the cochlea of chinchillas. (2004)
  • Author(s): Naito Y, Nakamura T, Nakagawa T, Iguchi F, Endo T, Fujino K, Kim TS, Hiratsuka Y, Tamura T, Kanemaru S, Shimizu Y, Ito J.
  • Journal Title: Neuroreport 15 Pages: 1-4
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Transplantation of neural stem cells into explants of rat inner ear. (2004)
  • Author(s): Fujino K, Kim TS, Nishida A, Nakagawa T, Omori K.Naito Y, Ito J.
  • Journal Title: Acta Otolaryngol Suppl 551 Pages: 31-33
• [Journal Article] Induction of cell proliferation and β-catenin expression in rat utricles in vitro. (2004)
  • Author(s): Kim TS, Nakagawa T, Lee JE, Fujino K, Iguchi F, Endo T, Naito Y, Omori K, Lefebvre PP, Ito J.
  • Journal Title: Acta Otolaryngol Suppl 551 Pages: 22-25
• [Journal Article] Expression of calretinin by fetal otocyst cells after transplantation into damaged rat utricle explants. (2004)
  • Author(s): Kim TS, Kojima K, Nishida A, Tashiro K, Lee JE, Fujino K, Nakagawa T, Iguchi F, Endo T, Naito Y, Omori K, Lefebvre PP, Ito J.
  • Journal Title: Acta Otolaryngol Suppl 551 Pages: 34-38
• [Journal Article] Transplantation of bone marrow stromal cells into the cochlea of chinchillas. (2004)
  • Author(s): Naito Y, Nakamura T, Nakagawa T, Iguchi F, Endo T, Fujino K, Kim TS, Hiratsuka Y, Tamura T, Kanemaru S, Shimizu Y, Ito J.
  • Journal Title: NeuroReport 15 Pages: 1-4
• [Journal Article] Role of the F-box protein Skp2 in cell proliferation in the developing auditory system in mice. (2003)
  • Author(s): Dong Y, Nakagawa T, Endo T, Kim TS, Iguchi F, Yamamoto N, Naito Y, Ito J.
  • Journal Title: Neuroreport 14 Pages: 759-761
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Trophic support of mouse inner ear by neural stem cell transplantation (2003)
  • Author(s): Iguchi F, Nakagawa T, Tateya I, Kim TS, Endo T, Taniguchi Z, Naito Y, Ito J.
  • Journal Title: Neuroreport 14 Pages: 77-80
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A novel technique for inducing local inner ear damage. (2003)
  • Author(s): Nakagawa T, Kim TS, Murai N, Endo T, Iguchi F, Tateya I, Yamamoto N, Naito Y, Ito J.
  • Journal Title: Hear Res 176 Pages: 122-127
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Fate of neural stem cells grafted into injured inner ears of mice. (2003)
  • Author(s): Tateya I, Nakagawa T, Iguchi F, Kim TS, Endo T, Yamada S, Kageyama R, Naito Y, Ito J.
  • Journal Title: Neuroreport 14 Pages: 1677-1681
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Trophic support of mouse inner ear by neural stem cell transplantation. (2003)
  • Author(s): Iguchi F, Nakagawa T, Tateya I, Kim TS, Endo T, Taniguchi Z, Naito Y, Ito J.
  • Journal Title: Neuroreport 14 Pages: 77-80
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Fujino K, Kim TS, Nishida A et al.: "Transplantation of neural stem cells into explants of rat inner ear"Acta Otolaryngol Suppl. 551. 31-33 (2004)
• [Publications] Kim TS, Nakagawa T, Lee JE, Fujino K et al.: "Induction of cell proliferation and β-catenin expression in rat utricles in vitro"Acta Otolaryngol Suppl. 551. 22-25 (2004)
• [Publications] Kim TS.Kojima K, Nishida A, Tashiro K, Lee JE, Fujino K et al.: "Expression of calretinin by fetal otocyst cells after transplantation into damaged rat utricle explants"Acta Otolaryngol Suppl. 551. 34-38 (2004)
• [Publications] Naito Y et al.: "Transplantation of bone marrow stromal cells into the cochlea of Chinchillas"NeuroReport. 15・1. 1-4 (2004)
• [Publications] 伊藤壽一 他: "内耳障害の再生医学的アプローチ"中西印刷. 244 (2003)