Attenuation of Progressive Hearing Loss in DBA/2J Mice by Epigenetic-Modifying Reagents

• Project/Area Number: 24592573
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: 独立行政法人国立病院機構(東京医療センター臨床研究センター)
• Principal Investigator: MUTAI Hideki 独立行政法人国立病院機構(東京医療センター臨床研究センター), 聴覚平衡覚研究部, 研究員 (60415891)
• Co-Investigator(Kenkyū-buntansha): MIYA Fuyuki 理化学研究所, 統合生命医科学研究センター, リサーチアソシエイト (50415311)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: エピジェネティクス / 加齢性難聴 / 亜鉛トランスポーター / 緑茶カテキン / EGCG / 難聴 / 薬剤標的 / 蝸牛 / マイクロアレイ

Outline of Final Research Achievements

Hearing loss can be caused by a combination of multiple environmental and genetic factors. In this study, we investigated whether epigenetic regulatory pathways could modulate a mouse model of progressive hearing loss.
Subcutaneous treatment of DBA/2J mice with a combination of epigenetic modifying reagents, methionine and valproic acid (M+V) significantly reduced the decline of hearing. Microarray analyses and subsequent quantitative RT-PCR and immunohistochemistry demonstrated up-regulation of a zinc importer, Zip4 in the cochlear tissues in association with attenuation of progressive hearing loss. Treatement of DBA mice with EGCG, a major green tea catechin with Zip4-inducing activity resulted in attenuation of hearing decline. This study suggests that epigenetic pathways can modify auditory function and demonstrates that zinc intake in the cochlea via Zip4 mediates the maintenance of mammalian hearing.

Research Products

• [Journal Article] Attenuation of Progressive Hearing Loss in DBA/2J Mice by Reagents that Affect Epigenetic Modifications Is Associated with Up-Regulation of the Zinc Importer Zip4 (2015)
  • Author(s): Mutai H., Miya F., Fujii M., Tsunoda T., Matsunaga T.
  • Journal Title: PLOS ONE Volume: 10 Issue: 4 Pages: e0124301-e0124301
  • DOI: 10.1371/journal.pone.0124301
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] High prevalence of CDH23 mutation in patients with congenital high-frequency recessive or sporadic hereditary hearing loss (2015)
  • Author(s): Mizutari K, Mutai H., Namba K., Miyanaga Y., Nakano A., Arimoto Y., Masuda S., Morimoto N., Sakamoto H., Kaga K., Matsunaga T.
  • Journal Title: Orphanet Journal of Rare Diseases Volume: 10 Issue: 1 Pages: 60-60
  • DOI: 10.1186/s13023-015-0276-z
  • Peer Reviewed / Open Access
• [Journal Article] A mutation in the heparin-binding site of noggin as a novel mechanism of proximal symphalangism and conductive hearing loss (2014)
  • Author(s): Masuda S., Namba K., Mutai H., Usui S., Miyanaga Y., Kaneko H., Matsunaga T.
  • Journal Title: Biochem Biophys Res Comm Volume: 447 Issue: 3 Pages: 196-502
  • DOI: 10.1016/j.bbrc.2014.04.015
  • Peer Reviewed / Open Access
• [Journal Article] Subgroups of enlarged vestibular aqueduct in relation with SLC26A4 mutations and hearing loss (2014)
  • Author(s): Yasuhide Okamoto, Hideki Mutai, Atsuko Nakano, Yukiko Arimoto, , Tomoko Sugiuchi, Sawako Masuda, Noriko Morimoto, Hirokazu Sakamoto, , Noboru Ogahara, Akira Takagi, Hidenobu Taiji, Kimitaka Kaga, Kaoru Ogawa, Tatsuo Matsunaga
  • Journal Title: Laryngoscope Volume: 124 Issue: 4
  • DOI: 10.1002/lary.24368
  • Peer Reviewed
• [Journal Article] GJB2-associated hearing loss undetected by hearing screening of newborns (2013)
  • Author(s): Shujiro B Minami, Hideki Mutai, Atsuko Nakano, Yukiko Arimoto, Hidenobu Taiji, Noriko Morimoto, Hideaki Sakata, Nodoka Adachi, Sawako Masuda, Hirokazu Sakamoto, Haruo Yoshida, Fujinobu Tanaka, Tomoko Sugiuchi, Kimitaka Kaga, Tatsuo Matsunaga
  • Journal Title: GENE Volume: 532 Issue: 1 Pages: 41-45
  • DOI: 10.1016/j.gene.2013.08.094
  • Peer Reviewed
• [Journal Article] Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: A cross-sectional, multi-center next-generation sequencing study. (2013)
  • Author(s): Mutai H, Suzuki N, Shimizu A, Torii C, Namba K, Morimoto N, Kudoh J, Kaga K, Kosaki K, Matsunaga T
  • Journal Title: Orphanet J. Rare Dis Volume: 8 Issue: 1 Pages: 172-172
  • DOI: 10.1186/1750-1172-8-172
  • Peer Reviewed
• [Journal Article] 次世代シークエンサーを用いた難聴の遺伝子診断に関する検討 (2013)
  • Author(s): 松永達雄、鈴木直大、務台英樹、難波一徳、加我君孝
  • Journal Title: Otol Japan Volume: 23 Pages: 903-907
  • NAID: 130005065221
• [Journal Article] Moderate hearing loss associated with a novel KCNQ4 non-truncating mutation located near the N-terminus of the pore helix. (2013)
  • Author(s): Takahisa Watabe,Tatsuo Matsunaga, Kazunori Namba, Hideki Mutai, Yasuhiro Inoue, Kaoru Ogawa
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 432 Issue: 3 Pages: 475-479
  • DOI: 10.1016/j.bbrc.2013.01.118
  • Peer Reviewed
• [Journal Article] Genetic analysis of PAX3 for diagnosis of Waardenburg syndrome type I (2013)
  • Author(s): Matsunaga T, Mutai H, Namba K, Morita N, Masuda S.
  • Journal Title: Acta Oto-Laryngologica Volume: 133 Issue: 4 Pages: 345-351
  • DOI: 10.3109/00016489.2012.744470
  • Peer Reviewed
• [Journal Article] Comorbid of GJB2 and WFS1 mutations in one family. (2012)
  • Author(s): Shujiro B Minami1, Sawako Masuda, Tomoko Usui, Hideki Mutai, Tatsuo Matsunaga.
  • Journal Title: Gene Volume: 501 Issue: 2 Pages: 193-197
  • DOI: 10.1016/j.gene.2012.03.060
  • Peer Reviewed
• [Journal Article] (2012)
  • Author(s): Matsunaga T, Mutai H, Kunishima S, Namba K, Morimoto N, Shinjo Y, Arimoto Y, Kataoka Y, Shintani T, Morita N, Sugiuchi T, Masuda S, Nakano A, Taiji H, Kaga K.
  • Journal Title: Clin Genet Volume: 82(5) Issue: 5 Pages: 425-32
  • DOI: 10.1111/j.1399-0004.2012.01897.x
  • Peer Reviewed
• [Presentation] DBA/2Jマウスのメチオニン・バルプロ酸による難聴進行抑制と候補標的遺伝子の亜鉛トランスポーターZip4 (2015)
  • Author(s): 務台、宮、藤井、角田、松永
  • Organizer: 日本エピジェネティクス研究会第9回年会
  • Place of Presentation: 一ツ橋学術総合センター（東京）
  • Year and Date: 2015-05-25 – 2015-05-26
• [Presentation] Attenuation of Progressive Hearing Loss in DBA/2J Mice by Epigenetic-Modifying Reagents Is Associated with Up-Regulation of the Zinc-Importer Zip4 /Slc39a4 (2015)
  • Author(s): Mutai, Miya, Fujii, Tsunoda, Matsunaga
  • Organizer: 北米耳鼻咽喉科学会第38回年会
  • Place of Presentation: ボルチモア（アメリカ合衆国メリーランド）
  • Year and Date: 2015-02-21 – 2015-02-25
• [Presentation] DBA/2Jマウスの難聴進行を抑制したエピジェネティクス調節剤の分子機構解析 (2014)
  • Author(s): 務台、藤井、松永
  • Organizer: 日本耳科学会第39回年会
  • Place of Presentation: 朱鷺メッセ （新潟）
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] Target-captured next generation sequencing of reported deafness genes reveals variability of genetic background of hereditary hearing loss in Japan (2013)
  • Author(s): Hideki Mutai, Naohiro Suzuki, Atsushi Shimizu, Chiharu Torii, Kazunori Namba, Jun Kudoh, Kenjiro Kosaki,Tatsuo Matsunaga
  • Organizer: 9th Molecular Biology of Hearing and Deafness
  • Place of Presentation: Stanford University, Palo Alto, California, USA
• [Presentation] 孤発例の先天性難聴患者における稀少難聴遺伝子変異の同定 (2013)
  • Author(s): 務台英樹、難波一徳、加我君孝、松永達雄
  • Organizer: 第23回日本耳科学会
  • Place of Presentation: 宮崎県宮崎市 シーガイアコンヴェンションセンター
• [Presentation] カスタムターゲットリシーケンスによる難聴関連遺伝子の変異探索 (2012)
  • Author(s): 鈴木直大、務台英樹、鳥居千春、清水厚志、宮冬樹、難波一徳、工藤純、小崎健次郎、松永達雄
  • Organizer: 第57回日本人類遺伝学会
  • Place of Presentation: 京王プラザホテル
• [Presentation] 難聴モデルDBA/2Jマウスに対するエピジェネティクス調節と聴力変化の検討 (2012)
  • Author(s): 務台英樹・藤井正人・松永達雄
  • Organizer: 第22回日本耳科学会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] Noggin蛋白質のin silico解析から推測されたSYM-1におけるアブミ骨を含む骨固着の分子病態 (2012)
  • Author(s): 難波一徳、務台英樹、増田佐和子、臼井智子、藤井正人、松永達雄
  • Organizer: 第22回日本耳科学会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] 次世代シークエンサーを用いた難聴の遺伝子診断に関する検討 (2012)
  • Author(s): 松永達雄、鈴木直大、務台英樹、難波一徳、加我君孝
  • Organizer: 第22回日本耳科学会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] 次世代シークエンスデータにおける難聴遺伝子変異の探索 (2012)
  • Author(s): 鈴木直大、務台英樹、松永達雄
  • Organizer: 第22回日本耳科学会
  • Place of Presentation: 名古屋国際会議場
• [Remarks] 国立病院機構東京医療センター感覚器センター 聴覚平衡覚研究部門 聴覚障害研究室
  • URL: http://www.kankakuki.go.jp/lab_c-1.html