In situ 3D imaging of the inner ear mitochondria and cochlear nerve

• Project/Area Number: 15K10744
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: The University of Tokyo
• Principal Investigator: KIKKAWA Yayoi 東京大学, 保健・健康推進本部, 助教 (00452350)
• Co-Investigator(Kenkyū-buntansha): 菊田 周 東京大学, 医学部附属病院, 講師 (00555865)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 内耳 / 鼻科学 / 解剖学 / 細胞生物学 / 有毛細胞 / 難聴 / 抗加齢医学 / 耳科学 / ミトコンドリア

Outline of Final Research Achievements

We developed a new analytical pipeline based on optical clearing of tissue, for the construction of a single-cell resolution map of the organ of Corti. Application of this method to samples from young, adult, and noise-exposed mice extracted essential information regarding cellular pathology, including longitudinal and radial spatial characteristics of cell loss, implying that multiple mechanisms underlie clustered cell loss.
Also, we studied protective effects of glycine and metformin against gentamicin induced ototoxicity on cultured cochlear explants. Results provided evidence of anti-apoptotic effect of metformin in parallel with prevention of ROS production and enhancement of cell viability.

Academic Significance and Societal Importance of the Research Achievements

近年の研究で、内耳障害のあらゆる面にミトコンドリアー活性酸素系が関わっていることが明らかになってきた。したがって、本研究は感音難聴や耳鳴制圧のための大きなブレークスルーをもたらす可能性がある。具体的には、この3DライブイメージングシステムによりNMN、Necrostatinなどのミトコンドリア保護剤などの神経保護薬剤の蝸牛保護能の評価が簡便に行えるようになれば、新たな防薬の開発も期待できる。
またこのmt-GFPマウスおよびBrainbowマウスのイメージングは、前庭系、嗅覚系、味覚系など様々な耳鼻咽喉科領域でのミトコンドリア・感覚神経回路の解明の基礎的手法・データとして利用が可能である。

Research Products

• [Journal Article] The adhesion molecule cadherin 11 is essential for acquisition of normal hearing ability through middle ear development in the mouse (2018)
  • Author(s): Kiyama Yuji、Kikkawa Yayoi S.、Kinoshita Makoto、Matsumoto Yu、Kondo Kenji、Fujimoto Chisato、Iwasaki Shinichi、Yamasoba Tatsuya、Manabe Toshiya
  • Journal Title: Laboratory Investigation Volume: 98 Issue: 11 Pages: 1364-1374
  • DOI: 10.1038/s41374-018-0083-y
  • Peer Reviewed / Open Access
• [Journal Article] Aging Is a Risk Factor for Utricular Dysfunction in Idiopathic Benign Paroxysmal Positional Vertigo (2018)
  • Author(s): Fujimoto Chisato、Kawahara Takuya、Kinoshita Makoto、Kikkawa Yayoi S.、Sugasawa Keiko、Yagi Masato、Yamasoba Tatsuya、Iwasaki Shinichi、Murofushi Toshihisa
  • Journal Title: Frontiers in Neurology Volume: 9 Pages: 1049-1049
  • DOI: 10.3389/fneur.2018.01049
  • Peer Reviewed / Open Access
• [Journal Article] Dorsal-zone-specific reduction of sensory neuron density in the olfactory epithelium following long-term exercise or caloric restriction (2018)
  • Author(s): Tuerdi Ayinuer、Kikuta Shu、Kinoshita Makoto、Kamogashira Teru、Kondo Kenji、Iwasaki Shinichi、Yamasoba Tatsuya
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 17300-17300
  • DOI: 10.1038/s41598-018-35607-w
  • Peer Reviewed / Open Access
• [Journal Article] Intravenous olfactory test latency correlates with improvement in post-infectious olfactory dysfunction (2017)
  • Author(s): Horikiri Kyohei、Kikuta Shu、Kanaya Kaori、Shimizu Yuya、Nishijima Hironobu、Yamasoba Tatsuya、Kondo Kenji
  • Journal Title: Acta Oto-Laryngologica Volume: 137 Issue: 10 Pages: 1083-1089
  • DOI: 10.1080/00016489.2017.1325005
  • Peer Reviewed
• [Journal Article] Repetitive Sinus-Related Symptoms May Accelerate the Progression of Chronic Maxillary Atelectasis (2017)
  • Author(s): Kikuta Shu、Horikiri Kyohei、Kanaya Kaori、Kagoya Ryoji、Kondo Kenji、Yamasoba Tatsuya
  • Journal Title: Case Reports in Otolaryngology Volume: 2017 Pages: 1-5
  • DOI: 10.1155/2017/4296195
  • Peer Reviewed / Open Access
• [Journal Article] 嗅覚障害の分類 (2017)
  • Author(s): 菊田 周
  • Journal Title: JOHNS Volume: 33 Pages: 157-160
• [Journal Article] 中枢性嗅覚障害 (2017)
  • Author(s): 菊田 周
  • Journal Title: JOHNS Volume: 33 Pages: 1505-1508
• [Journal Article] Longer latency of sensory response to intravenous odor injection predicts olfactory neural disorder. (2016)
  • Author(s): Kikuta S, Matsumoto Y, Kuboki A, Nakayama T, Asaka D, Otori N, Kojima H, Sakamoto T, Akinori K, Kanaya K, Ueha R, Kagoya R, Nishijima H, Toma-Hirano M, Kikkawa Y, Kondo K, Tsunoda K, Miyaji T, Yamaguchi T, Kataoka K, Mori K, Yamasoba T.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 35361-35361
  • DOI: 10.1038/srep35361
  • NAID: 130006708720
  • Peer Reviewed / Open Access
• [Journal Article] Cigarette Smoke Delays Regeneration of the Olfactory Epithelium in Mice. (2016)
  • Author(s): Ueha R, Ueha S, Sakamoto T, Kanaya K, Suzukawa K, Nishijima H, Kikuta S, Kondo K, Matsushima K, Yamasoba T.
  • Journal Title: Neurotox Res Volume: 30 Issue: 2 Pages: 213-224
  • DOI: 10.1007/s12640-016-9617-5
  • Peer Reviewed
• [Journal Article] Defects in Synaptic Plasticity, Reduced NMDA-Receptor Transport, and Instability of Postsynaptic Density Proteins in Mice Lacking Microtubule-Associated Protein 1A. (2015)
  • Author(s): Takei Y, Kikkawa YS, Atapour N, Hensch TK, Hirokawa N
  • Journal Title: J Neurosci Volume: 35 Issue: 47 Pages: 15539-54
  • DOI: 10.1523/jneurosci.2671-15.2015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differences in Postoperative Hearing Outcomes and Vertigo in Patients with Otosclerosis Treated with Laser-Assisted Stapedotomy versus Stapedectomy. (2015)
  • Author(s): Sakamoto T, Kikuta S, Kikkawa YS, Tsutsumiuchi K, Kanaya K, Fujimaki Y, Ueha R, Saito Y, Yamasoba T.
  • Journal Title: ORL J Otorhinolaryngol Relat Spec. Volume: 77 Issue: 5 Pages: 287-93
  • DOI: 10.1159/000439177
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Safety, reliability, and operability of cochlear implant electrode arrays coated with biocompatible polymer. (2015)
  • Author(s): Kinoshita M, Kikkawa YS, Sakamoto T, Kondo K, Ishihara K, Konno T, Pawsey N, Yamasoba T.
  • Journal Title: Acta Otolaryngol Volume: 135 Issue: 4 Pages: 320-7
  • DOI: 10.3109/00016489.2014.990580
  • Peer Reviewed
• [Journal Article] Prognostic factors for long-term hearing preservation after canal-tympanoplasty for congenital aural atresia. (2015)
  • Author(s): Sakamoto T, Kikuta S, Kikkawa YS, Kinoshita M, Saito Y, Kobayashi K, Kakigi A, Suzuki M, Yamasoba T
  • Journal Title: Europian Archives of Otorhinolaryngology Volume: 272 Issue: 11 Pages: 3151-6
  • DOI: 10.1007/s00405-014-3164-6
  • Peer Reviewed
• [Journal Article] Sensory deprivation disrupts homeostatic regeneration of newly generated olfactory sensory neurons after injury in adult mice. (2015)
  • Author(s): Kikuta S, Sakamoto T, Nagayama S, Kanaya K, Kinoshita M, Kondo K, Tsunoda K, Mori K, Yamasoba T.
  • Journal Title: J Neurosci. Volume: 35 Issue: 6 Pages: 2657-2673
  • DOI: 10.1523/jneurosci.2484-14.2015
  • Peer Reviewed / Open Access
• [Presentation] メトフォルミンの蝸牛有毛細胞保護効果についての検討 (2018)
  • Author(s): 吉川弥生、樫尾明憲、木下淳、山岨達也
  • Organizer: 第28回日本耳科学会総会・学術講演会
• [Presentation] ミトコンドリア蛍光 (mtGFP) マウスを用いた蝸牛有毛細胞内ミトコンドリア動態の検討 (2017)
  • Author(s): 吉川弥生、浦田真次、木下 淳、山岨達也
  • Organizer: 第27回日本耳科学会総会・学術講演会
• [Presentation] 第24回日本鼻科学会賞受賞講演：Longer latency of sensory response to intravenous odor injection predicts olfactory neural disorder (2017)
  • Author(s): 菊田 周
  • Organizer: 第56回日本鼻科学会
  • Invited
• [Presentation] Longer latency of sensory response to intravenous odor injection predicts olfactory neural disorder (2017)
  • Author(s): Kikuta Shu
  • Organizer: IFOS, ENT world congress 2017
• [Presentation] 菊田 周、久保木章仁、金谷佳織、水嶋 優、清水裕也、上羽瑠美、西嶌大宣、近藤健二、山岨達也 (2017)
  • Author(s): 嗅上皮の恒常性維持における鼻汁中インスリンの防御的役割
  • Organizer: 日本鼻科学会総会
• [Presentation] 吉川 弥生, 岩崎 真一, 西 敏子, 鴨頭 輝, 木下 淳, 鈴木さやか, 江上 直也, 藤本 千里, 牛尾 宗貴, 菅澤 恵子, 山岨 達也 (2017)
  • Author(s): 下肢振動覚障害がラバー負荷重心動揺検査に及ぼす影響の検討
  • Organizer: 第76回日本めまい平衡医学会総会・学術講演会