オートファジーの内耳生理機能および加齢性内耳障害への関与

• Project Area: Multidisciplinary research on autophagy: from molecular mechanisms to disease states
• Project/Area Number: 26111506
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: 藤本 千里 東京大学, 医学部附属病院, 助教 (60581882)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000); Fiscal Year 2015: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2014: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
• Keywords: 内耳 / オートファジー / 神経科学 / 耳鼻咽喉科学

Outline of Annual Research Achievements

内耳の感覚細胞である有毛細胞は、さまざまな特化された微細構造を持ち、音や加速度といった機械的刺激を生体内の電気信号に変換するという非常に巧妙な機能を担うが、細胞分裂せず一度障害を受けると機能的再生が困難なため、障害の多くは不可逆的である。このため、有毛細胞においては、細胞の恒常性維持・機能維持が特に重要と考えられる。
本研究では、細胞の恒常性維持に重要であるオートファジーが、マウスの聴覚機能に重要な役割を果たすことを明らかにした。
オートファジーに必須の分子であるautophagy-related 5（Atg5）を有毛細胞にて欠損させた遺伝子改変マウス（Atg5flox/flox;Pou4f3-Creマウス）を作製し、有毛細胞におけるオートファジー活性が聴覚機能および細胞形態に及ぼす影響を検討した。有Atg5flox/flox;Pou4f3-Creマウスは先天性の高度難聴を呈し、有毛細胞内にユビキチン-p62陽性封入体形成を認めた。また、Atg5flox/flox;Pou4f3-Creマウス有毛細胞の組織学的検討では、14日齢において聴毛の変性、および一部の細胞の脱落を認めた。8週齢においては、有毛細胞の変性がさらに進行していた。
本研究により、有毛細胞における恒常的オートファジーは聴覚機能および細胞形態の維持に重要であることが示された。オートファジーと聴覚障害の病態形成との関連性について、さらなる研究の進展が期待される。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Autophagy is essential for hearing in mice. (2017)
  • Author(s): Fujimoto C, Iwasaki S, Urata S, Morishita H, Sakamaki Y, Fujioka M, Kondo K, Mizushima N, Yamasoba T
  • Journal Title: Cell Death Dis Volume: 印刷中 Issue: 5 Pages: e2780-e2780
  • DOI: 10.1038/cddis.2017.194
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effect of Noisy Galvanic Vestibular Stimulation on Ocular Vestibular-Evoked Myogenic Potentials to Bone-Conducted Vibration (2017)
  • Author(s): Iwasaki S, Karino S, Kamogashira T, Togo F, Fujimoto C, Yamamoto Y, Yamasoba T
  • Journal Title: Front Neurol Volume: 8 Pages: 26-26
  • DOI: 10.3389/fneur.2017.00026
  • Peer Reviewed / Open Access
• [Journal Article] Manganese superoxide dismutase influences the extent of noise-induced hearing loss in mice. (2017)
  • Author(s): Tuerdi A, Kinoshita M, Kamogashira T, Fujimoto C, Iwasaki S, Shimizu T, Yamasoba T
  • Journal Title: Neurosci Lett Volume: 642 Pages: 123-128
  • DOI: 10.1016/j.neulet.2017.02.003
  • Peer Reviewed / Open Access
• [Journal Article] Functionally and morphologically damaged mitochondria observed in auditory cells under senescence-inducing stress. (2017)
  • Author(s): Kamogashira T, Hayashi K, Fujimoto C, Iwasaki S, Yamasoba T
  • Journal Title: NPJ Aging Mech Dis Volume: 3 Issue: 1 Pages: 2-2
  • DOI: 10.1038/s41514-017-0002-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Noisy galvanic vestibular stimulation induces a sustained improvement in body balance in elderly adults (2016)
  • Author(s): Fujimoto C, Yamamoto Y, Kamogashira T, Kinoshita M, Egami N, Uemura Y, Togo F, Yamasoba T, Iwasaki S
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 37575-37575
  • DOI: 10.1038/srep37575
  • Peer Reviewed / Open Access
• [Journal Article] Vestibular Evoked Myogenic Potentials in Vestibular Migraine: Do They Help Differentiating From Menière's Disease? (2016)
  • Author(s): Inoue A, Egami N, Fujimoto C, Kinoshita M, Yamasoba T, Iwasaki S
  • Journal Title: Ann Otol Rhinol Laryngol Volume: 125 Pages: 931-937
  • Peer Reviewed
• [Journal Article] Denervation of nasal mucosa induced by posterior nasal neurectomy suppresses nasal secretion, not hypersensitivity, in an allergic rhinitis rat model. (2016)
  • Author(s): Nishijima H, Kondo K, Toma-Hirano M, Iwasaki S, Kikuta S, Fujimoto C, Ueha R, Kagoya R, Yamasoba T
  • Journal Title: Lab Invest Volume: 96 Issue: 9 Pages: 981-993
  • DOI: 10.1038/labinvest.2016.72
  • Peer Reviewed
• [Journal Article] Association of the upregulated expression of focal adhesion kinase with poor prognosis and tumor dissemination in hypopharyngeal cancer. (2016)
  • Author(s): Omura G, Ando M, Saito Y, Kobayashi K, Yoshida M, Ebihara Y, Kanaya K, Fujimoto C, Sakamoto T, Kondo K, Asakage T, Yamasoba T
  • Journal Title: Head Neck. Volume: Published on line Issue: 8 Pages: 1164-1169
  • DOI: 10.1002/hed.24176
  • Peer Reviewed
• [Journal Article] Human Papillomavirus 16 Physical Status and the TP53 Codon 72 Polymorphism in Japanese HPV-Positive Oropharyngeal Cancer Patients. (2016)
  • Author(s): Saito Y, Ando M, Fujimoto C, Omura G, Kobayashi K, Asakage T, Yamasoba T.
  • Journal Title: ORL J Otorhinolaryngol Relat Spec. Volume: 78(1) Issue: 1 Pages: 46-54
  • DOI: 10.1159/000442354
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characteristics of vertigo and the affected vestibular nerve systems in idiopathic bilateral vestibulopathy. (2016)
  • Author(s): Fujimoto C, Kinoshita M, Kamogashira T, Egami N, Sugasawa K, Yamasoba T, Iwasaki S.
  • Journal Title: Acta Otolaryngol. Volume: 136(1) Issue: 1 Pages: 43-47
  • DOI: 10.3109/00016489.2015.1082193
  • Peer Reviewed
• [Journal Article] 重心動揺検査の現状と将来展望 ラバー負荷検査の有用性と今後の展望 (2016)
  • Author(s): 藤本千里
  • Journal Title: Equilibrium Res Volume: 75 Pages: 142-146
  • Peer Reviewed
• [Journal Article] めまい-新しい流れとその周辺-】 新しい検査・解釈 重心動揺計 (2016)
  • Author(s): 藤本千里
  • Journal Title: JOHNS Volume: 32 Pages: 33-35
• [Journal Article] Involvement of vestibular organs in idiopathic sudden hearing loss with vertigo: An analysis using oVEMP and cVEMP testing. (2015)
  • Author(s): Fujimoto C, Egami N, Kinoshita M, Sugasawa K, Yamasoba T, Iwasaki S.
  • Journal Title: Clin Neurophysiol. Volume: 126 Issue: 5 Pages: 1033-8
  • DOI: 10.1016/j.clinph.2014.07.028
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The effect of center-of-pressure power spectrum in foam posturography. (2015)
  • Author(s): Fujimoto C, Egami N, Demura S, Yamasoba T, Iwasaki S.
  • Journal Title: Neurosci Lett. Volume: 585 Pages: 92-7
  • DOI: 10.1016/j.neulet.2014.11.033
  • Peer Reviewed
• [Journal Article] Clinical Characteristics of Patients With Abnormal Ocular/Cervical Vestibular Evoked Myogenic Potentials in the Presence of Normal Caloric Responses. (2015)
  • Author(s): Iwasaki S, Fujimoto C, Kinoshita M, Kamogashira T, Egami N, Yamasoba T.
  • Journal Title: Ann Otol Rhinol Laryngol. Volume: 124 Pages: 458-65
  • Peer Reviewed
• [Journal Article] Reactive Oxygen Species, Apoptosis, and Mitochondrial Dysfunction in Hearing Loss. (2015)
  • Author(s): Kamogashira T, Fujimoto C, Yamasoba T
  • Journal Title: Biomed Research International Volume: 2015 Pages: 617207-617207
  • DOI: 10.1155/2015/617207
  • Peer Reviewed / Open Access
• [Journal Article] Noisy vestibular stimulation improves body balance in bilateral vestibulopathy. (2014)
  • Author(s): Iwasaki S, Yamamoto Y, Togo F, Kinoshita M, Yoshifuji Y, Fujimoto C, Yamasoba T.
  • Journal Title: Neurology Volume: 82 Issue: 11 Pages: 969-975
  • DOI: 10.1212/wnl.0000000000000215
  • Peer Reviewed
• [Journal Article] Developmental changes in the protective effect of exogenous brain-derived neurotrophic factor and neurotrophin-3 against ototoxic drugs in cultured rat vestibular ganglion. (2014)
  • Author(s): Inoue A, Iwasaki S, Fujimoto C, Nakajima T, Yamasoba T
  • Journal Title: Cell Tissue Res Volume: 356 Issue: 2 Pages: 299-308
  • DOI: 10.1007/s00441-014-1813-0
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Oxidative stresses and mitochondrial dysfunction in age-related hearing loss. (2014)
  • Author(s): Fujimoto C, Yamasoba T.
  • Journal Title: Oxid Med Cell Longev Volume: 2014 Pages: 582849-582849
  • DOI: 10.1155/2014/582849
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Power spectral analysis of postural sway during foam posturography in patients with peripheral (2014)
  • Author(s): Fujimoto C, Kamogashira T, Kinoshita M, Egami N, Sugasawa K, Demura S, Yamasoba T, Iwasaki S.
  • Journal Title: Otol Neurotol. Volume: 35 Issue: 10 Pages: e317-e323
  • DOI: 10.1097/mao.0000000000000554
  • Peer Reviewed
• [Journal Article] Fujimoto C, Yamasoba T, Iwasaki S. Idiopathic latent vestibulopathy: a clinical entity as a cause of chronic postural instability. (2014)
  • Author(s): Fujimoto C, Yamasoba T, Iwasaki S.
  • Journal Title: Eur Arch Otorhinolaryngol Volume: 272 Issue: 1 Pages: 43-49
  • DOI: 10.1007/s00405-013-2834-0
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Video head impulse testにおけるcatch-up saccadeの性状と温度刺激検査におけるcanal paresisとの関連 (2016)
  • Author(s): 藤本千里、岩崎真一、鴨頭輝、木下淳、鈴木さやか、江上直也、牛尾宗貴、菅澤恵子、山岨達也
  • Organizer: 第75回日本めまい平衡医学会総会・学術講演会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2016-10-27
• [Presentation] 温度刺激検査で一側半規管麻痺を呈した症例におけるvideo head impulse testのcatch-up saccadeについて (2016)
  • Author(s): 藤本千里、岩崎真一、鴨頭輝、木下淳、鈴木さやか、江上直也、牛尾宗貴、山岨達也
  • Organizer: 第26回日本耳科学会・学術講演会
  • Place of Presentation: ホテル国際21(長野県・長野市)
  • Year and Date: 2016-10-05
• [Presentation] 経皮的ノイズ前庭電気刺激が健常者の立位体平衡機能に及ぼす影響 (2016)
  • Author(s): 藤本千里、岩崎真一、鴨頭輝、木下淳、江上直也、山岨達也
  • Organizer: 第16回日本抗加齢医学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-06-10
• [Presentation] Effect of noisy galvanic vestibular stimulation on gait performance in patients with bilateral vestibulopathy. (2016)
  • Author(s): Chisato Fujimoto, Shinichi Iwasaki, Teru Kamogashira, Makoto Kinoshita, Naoya Egami, Yukari Uemura, Fumiharu Togo, Yoshiharu Yamamoto and Tatsuya Yamasoba
  • Organizer: 29th Barany Society Meeting
  • Place of Presentation: Seoul (Korea)
  • Year and Date: 2016-06-05
  • Int'l Joint Research
• [Presentation] 経皮的ノイズ前庭電気刺激による長期的な静的体平衡機能改善効果 (2016)
  • Author(s): 藤本千里、岩崎真一、鴨頭輝、木下淳、江上直也、山岨達也
  • Organizer: 第117回 日本耳鼻咽喉科学会・学術講演会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2016-05-18
• [Presentation] 経皮的ノイズ前庭電気刺激による体平衡機能改善効果 (2016)
  • Author(s): 藤本千里、岩崎真一、鴨頭輝、木下淳、江上直也、山岨達也
  • Organizer: 第15回姿勢と歩行研究会
  • Place of Presentation: 興和株式会社 東京支店（東京都・中央区）
• [Presentation] THE EFFECT OF AGINGON THE CENTER-OF-PRESSURE POWER SPECTRUMIN FOAM POSTUROGRAPHY (2015)
  • Author(s): Chisato Fujimoto, Shinichi Iwasaki, Naoya Egami and Tatsuya Yamasoba
  • Organizer: 13th Asia-Oceania ORL-HNS Congress
  • Place of Presentation: 台北市
  • Year and Date: 2015-03-19 – 2015-03-22
• [Presentation] 内耳有毛細胞におけるオートファジーの役割 (2014)
  • Author(s): 藤本千里
  • Organizer: 第8回オートファジー研究会
  • Place of Presentation: 札幌市
  • Year and Date: 2014-11-11 – 2014-11-12
• [Presentation] 特発性両側性末梢前庭機能低下症の臨床経過と障害部位に関する検討 (2014)
  • Author(s): 藤本千里、木下淳、鴨頭輝、江上直也、牛尾宗貴、菅澤恵子、山岨達也、岩崎真一
  • Organizer: 第73回日本めまい平衡医学会総会・学術講演会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-11-05 – 2014-11-07
• [Presentation] 酸素消費速度を指標としたマウスコルチ器のミトコンドリア機能評価 (2014)
  • Author(s): 藤本千里、鴨頭輝、木下淳、岩崎真一、山岨達也
  • Organizer: 第24回日本耳科学会総会・学術講演会
  • Place of Presentation: 新潟市
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] 末梢前庭障害患者におけるラバー負荷重心動揺検査のパワースペクトル解析 (2014)
  • Author(s): 藤本千里、岩崎真一、鴨頭輝、木下淳、江上直也、菅澤恵子、山岨達也
  • Organizer: 第115回日本耳鼻咽喉科学会総会・学術講演会
  • Place of Presentation: 福岡市
  • Year and Date: 2014-05-14 – 2014-05-17