Regeneration of lacrimal grand by the induction of highly-ordered acinus branching

• Project/Area Number: 19592034
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: YOKOI Norihiko Kyoto Prefectural University of Medicine, 医学研究科, 准教授 (60191491)
• Co-Investigator(Kenkyū-buntansha): KAWASAKI Satoshi 京都府立医科大学, 医学研究科, 助教 (60347458) ; MATSUDA Akira 現順天堂大学, 医学部・医学研究科, 准教授 (00312348)
• Research Collaborator: FUKUOKA Fukuoka 京都府立医科大学, 医学研究科, 大学院生 ; TANIOKA Hidetoshi 京都府立医科大学, 医学研究科, 研究生
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2007: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 涙腺 / 移植 / 再生医療 / 発生・分化 / 涙液 / 生理学 / 移植・再生医療 / 細胞・組織 / miRNA / エピジェネティクス / メチル化 / 機能的RNA / 角膜上皮細胞

Research Abstract

これまでStevens-Johns症候群等の重症眼表面疾患においては涙液の量的・質的双方の異常がその病態形成に大きく関与するとは考えられていたものの、再生治療的な観点からは注目されていなかった。角膜上皮や口腔粘膜上皮細胞が平面状の上皮シートの状態で治療に使用できる事に対し、涙腺組織は複雑な3次元構造をとるため培養そのものが極めて困難であるとされるためである。今回の我々のチャレンジはこの点についてのブレークスルーを得ることを目的としたものである。結果として、涙腺上皮細胞はコラーゲンゲル内である程度の3次元構造を取りうることがわかった。実際にin vivoの涙腺組織のもつ複雑かつ機能的な組織構築をin vitroで再構成するには多くの機能性因子の同定が必要と考えられた。また我々は涙液の質的・量的異常の検出のためにいくつかの臨床機器およびそれに関連したソフトウエアの開発についても同時に行った。さらにそれらを用いて涙液油層の動的挙動の生理物理的な原理を解明するために流体力学モデル(Vogt モデル)を考案し、さらにクロスコリレーション法を応用することにより実際の臨床の場でリアルタイムに涙液油層伸展の解析を行なうことに成功した。さらにこの方法を用いて、ドライアイのスクリーニングや重症度評価が油層伸展初速度という非侵襲的なパラメーターによって評価できることを見出した。さらに油層伸展初速度を決定する因子について重回帰分析を行なったところ、眼表面の涙液貯留量がもっとも大きく関与することが明らかとなった。この新しい評価法は侵襲的、半定量的な従来の評価法に比べると大きな進歩であり、臨床のみならず動物実験の場でも今後の活用性が期待できる。

Research Products

• [Journal Article] Surgery of the conjunctiva (2008)
  • Author(s): Yokoi N, Inatomi T, Kinoshita S.
  • Journal Title: Dev Ophthalmol 41 Pages: 138-58
• [Journal Article] Rheology of tear film lipid layer spread in normal and aqueous tear deficient dry eyes (2008)
  • Author(s): Yokoi N, Yamada H, Mizukusa Y, Bron AJ, Tiffany JM, Kato T, Kinoshita S.
  • Journal Title: Invest Ophthalmol Vis Sci 49(12) Pages: 5319-5324
• [Journal Article] High-affinity IgE receptor-s chain expression in human mast cells (2008)
  • Author(s): Matsuda A, Okayama Y, Ebinhara N, Yokoi N, Gao P, Hamuro J, Hopkin JMKinoshita S.
  • Journal Title: J. Immunol. Methods 336 Pages: 229-234
• [Journal Article] Rheology of tear film lipid layer spread in normal and aqueous tear deficient dry eyes. (2008)
  • Author(s): Yokoi N., et al
  • Journal Title: Invest Ophthalmol Vis Sci 49 Pages: 5319-5324
  • Peer Reviewed
• [Journal Article] Human conjunctival epithelial cells express functional Toll-like receptor5 (2008)
  • Author(s): Kojima K, Ueta M, Hamuro J, Hozono Y, Kawasaki S, Yokoi N, Kinoshita S
  • Journal Title: Br J Ophthalmol 92 Pages: 411-416
  • Peer Reviewed
• [Journal Article] Sutureless amniotic membrane transplantation for ocular surface reconstruction with a chemically defined bioadhesive (2008)
  • Author(s): Takaoka M, Nakamura T, Sugai H, Bentley AJ, Nakajima N, Fullwood NJ, Yokoi N, Hyon SH, Kinoshita S
  • Journal Title: Biomaterials 29 Pages: 2923-2931
  • Peer Reviewed
• [Journal Article] A newly-developed video-meibography system featuring anewly-designed probe (2007)
  • Author(s): Yokoi N, Komuro A, YamK, Kinoshita S.
  • Journal Title: Jpn J Ophthalmol 51(1) Pages: 53-56
• [Journal Article] A new grading system for the evaluation of chronic ocular manifestations in patients witStevens-Johnson syndrome (2007)
  • Author(s): Sotozono C, Ang LPK, Koizumi N,Higashihara H, Ueta M, Inatomi T,Yokoi N, Kaido M, Murato D, ShimazakJ, Tsubota K, Yamada M, Kinoshia S.
  • Journal Title: Ophthalmology 114(7) Pages: 1294-1302
• [Journal Article] Methodologies to diagnose and monitor dry eye disease : Reportthe diagnostic methodology subcommittee of the internatdry eye workshop (2007) (2007)
  • Author(s): Bron AJ, Abelson MB, E, Tomlinson A, Yokoi N, Smith JA, Begley C, Caffery B, Nichols K, Schaumberg D, Schein O, Calonge MBaudouin C, Goto E, Grus F, Paugh J.
  • Journal Title: Ocul Surf 5(2) Pages: 108-152
• [Journal Article] Methodologies to diagnose and monitor dry eye disease: Report of the diagnostic methodology subcommittee of the international dry eye workshop (2007)
  • Author(s): Bron AJ, Abelson MB, Ousler G, Pearce E, Tomlinson A, Yokoi N, Smith JA, Begley C, Caffery B, Nichols K, Schaumberg D, Schein O, Calonge M, Baudouin C, Goto E, Grus F, Paugh J
  • Journal Title: Ocul Surf 5 Pages: 108-152
  • Peer Reviewed
• [Journal Article] Hyperexpression of the high-affinity IgE receptor-β chain in chronic allergic keratoconjunctivitis
  • Author(s): Matsuda A, Okayama Y, Ebihara N, Yokoi N, Hamuro J, Walls AF, Ra C, Hopkin JM, Kinoshita S.
  • Journal Title: Invest Ophthalmol Vis Sci (in press)
• [Journal Article] Predicted phenotypes of dry eye : Proposed consequences of its natural history
  • Author(s): Bron AJ, Yokoi N, Gaffney Eamonn, Tiffany JM.
  • Journal Title: Ocular Surface (in press)
• [Journal Article] A mass and solute balance model for tear volume and osmolarity in the normal and the dry eye prog
  • Author(s): Gaffney Eamonn, Tiffany JM, Yokoi N, Bron AJ
  • Journal Title: Retina and Eye Res (in press)
• [Journal Article] Filament in filamentary keratitis
  • Author(s): Tanioka H, Yokoi N, Komuro A, Shimamoto T, Kawasaki S, Matsuda A, Kinoshita S.
  • Journal Title: Invest Ophthalmol Vis Sci (in press)
• [Journal Article] Predicted phenotypes of dry eye : Proposed consequences of its natural history.
  • Author(s): Bron A. J., et al
  • Journal Title: Ocular Surface (In press)
  • Peer Reviewed
• [Journal Article] A mass and solute balance model for tear volume and osmolarity in the normal and the dry eye prog.
  • Author(s): Gaffney E., et al
  • Journal Title: Retina and Eye Res (In press)
  • Peer Reviewed
• [Presentation] A new surgery for punctal occlusion using fibrous tissue from under the caruncle (2008)
  • Author(s): Yokoi N, Komuro A, Nishii M.
  • Organizer: American Academy of Ophthalmology 2008 Joint Meeting with the European Society of Ophthalmology
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2008-11-09
• [Presentation] A new surgery for punctal occlusion (2008)
  • Author(s): Yokoi N.
  • Organizer: 2008 Japan-Korea Joint Cornea Conference
  • Place of Presentation: Seoul
  • Year and Date: 2008-10-03
• [Presentation] Advanced conjunctival surgeries for the improvement of dry eye and dry-eye associated disorders (2008)
  • Author(s): Yokoi N.
  • Organizer: World Ophthalmology Congress 2008
  • Place of Presentation: Hong Kong
  • Year and Date: 2008-07-01
• [Presentation] Clinical compatibility of multipurpose solutions with silicone hydrogel contact lenses (2008)
  • Author(s): Yokoi N.
  • Organizer: World Ophthalmology Congress 2008
  • Place of Presentation: Hong Kong
  • Year and Date: 2008-07-01
• [Presentation] Applicability of a new tear stability analysis system for the screening of dry eye (2008)
  • Author(s): Shimamoto T, Yokoi N, Maruyama K, Komuro A, Nishii M, Kinoshita S.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: Fort Lauderdale, USA
  • Year and Date: 2008-05-01
• [Presentation] Retension of long-acting carteolol alginate ophthalmic solution on the human ocular surface (2008)
  • Author(s): Komuro A, Yokoi N, Maruyama K, Kinoshita S.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: Fort Lauderdale, USA
  • Year and Date: 2008-04-28
• [Presentation] Composition of the corneal filament in filamentary keratitis on immunohistochemical examination (2008)
  • Author(s): Tanioka H, Yokoi N, Shimamoto T, Komuro A, Kawasaki S, Matsuda M, Kinoshita S.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: Fort Lauderdale, USA
  • Year and Date: 2008-04-28
• [Presentation] Sex differences in meibomian gland physiology (2008)
  • Author(s): Suzuki T, Yokoi N, Komuro A, Kinoshita S.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: Fort Lauderdale, USA
  • Year and Date: 2008-04-27
• [Presentation] A newly developed biodegradable punctal plug with controlled bFGF release for permanent lacrimal punctal occlusion (2008)
  • Author(s): Hori K, Hamuro J, Sotozono C, Kawasaki S, Yokoi N, Ueda H, Tabata Y, Kinoshita S.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: Fort Lauderdale, USA
  • Year and Date: 2008-04-27
• [Presentation] The improved surgical technique for conjunctivochalasis (2007)
  • Author(s): Sonomura Y, Yokoi N, Komuro A, Nishii M, Inagaki K, Chihara H, Kinoshita S.
  • Organizer: 5th international Conference on the Lacrimal Gland, Tear Film, Ocular Surface and Dry Eye Syndromes : Basic Science and Clinical Relevance
  • Place of Presentation: Taormina, Sicily, Italy
  • Year and Date: 2007-09-07
• [Presentation] Long-term results of superior conjunctivochalasis operation for treating superior limbic keratoconjunctivitis (2007)
  • Author(s): Komuro A, Yokoi N, Maruyama K, Kinoshita S.
  • Organizer: 5th international Conference on the Lacrimal Gland, Tear Film, Ocular Surface and Dry Eye Syndromes : Basic Science and Clinical Relevance
  • Place of Presentation: Taormina, Sicily, Italy
  • Year and Date: 2007-09-07
• [Presentation] A new surgical punctal occlusion using fibrous tissue under the lacrimal caruncle (2007)
  • Author(s): Yokoi N, Chihara H, Nishii M, Komuro A, Shimamoto T, Kinoshita S.
  • Organizer: 5th international Conference on the Lacrimal Gland, Tear Film, Ocular Surface and Dry Eye Syndromes : Basic Science and Clinical Relevance
  • Place of Presentation: Taormina, Sicily, Italy
  • Year and Date: 2007-09-07
• [Presentation] Imprementation of a new questionnaire into the recently revised Japanese dry eye diagnostic criteria (2007)
  • Author(s): Ward S, Dogru M, Wakamatsu T, Ebrahim O, Kaido M, Matsumoto Y, Yokoi N, Ueda M, Tsuyama A, Tsubota K.
  • Organizer: 5th international Conference on the Lacrimal Gland, Tear Film, Ocular Surface and Dry Eye Syndromes : Basic Science and Clinical Relevance
  • Place of Presentation: Taormina, Sicily, Italy
  • Year and Date: 2007-09-07
• [Presentation] A new surgical punctal occlusion using fibrous tissue under the lacrimal caruncle (2007)
  • Author(s): Yokoi N, Chihara H, Nishii M, Komuro A, Shimamoto T, Kinoshita S
  • Organizer: 5th international Conference on the Lacrimal Gland, Tear Film, Ocular Surface and Dry Eye Syndromes: Basic Science and Clinical Relevance
  • Place of Presentation: Taormina, Sicily, Italy
  • Year and Date: 2007-09-07
• [Presentation] Immunohistochemical investigation of the filament in filamentary keratitis (2007)
  • Author(s): Tanioka H, Yokoi N, Komuro A, Shimamoto T, Kawasaki S, Matsuda A, Kinoshita S.
  • Organizer: 5th international Conference on the Lacrimal Gland, Tear Film, Ocular Surface and Dry Eye Syndromes : Basic Science and Clinical Relevance
  • Place of Presentation: Taormina, Sicily, Italy
  • Year and Date: 2007-09-06
• [Presentation] A new interference-based in vitro technique for the wettability assessment of soft contact lenses (2007)
  • Author(s): Maruyama K, Yokoi N, Kinoshita S.
  • Organizer: British Contact Lens Association
  • Place of Presentation: Manchester, England
  • Year and Date: 2007-06-03
• [Presentation] Evaluation of wettability in MPS by interference-based in vitro techniquea (2007)
  • Author(s): Sakai R, Maruyama K, Yokoi N, Kinoshita S.
  • Organizer: British Contact Lens Association
  • Place of Presentation: Manchester, England
  • Year and Date: 2007-06-03
• [Presentation] New interferometric-based in vitro technique applicable to the assessment of wettability of contact lenses (2007)
  • Author(s): Maruyama K, Yokoi N, Kinoshita S.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: Fort Lauderdale, USA
  • Year and Date: 2007-05-10
• [Presentation] The cyclic change of Meibomian gland physiology during the menstrual cycle (2007)
  • Author(s): Suzuki T, Yokoi N, Komuro A, Kinoshita S.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: Fort Lauderdale, USA
  • Year and Date: 2007-05-06
• [Presentation] Development of automated rheological analysis for tear film lipid layer spread using the cross-correlation method (2007)
  • Author(s): Yokoi N, Yamada H, Maruyama K, Mizukusa Y, Bron AJ, Tiffany JM, Kinoshita S.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: Fort Lauderdale, USA
  • Year and Date: 2007-05-06
• [Presentation] Development of automated rheological analysis for tear film lipidlayer spread using the cross-correlation method. (2007)
  • Author(s): Yokoi N., et al
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: Fort Lauderdale, USA
  • Year and Date: 2007-05-06
• [Presentation] ドライアイにおける涙液油層の動態変化. シンポジウム7新世界ドライアイ診断基準とドライアイ診断における考え方はこう変わった (2007)
  • Author(s): 横井則彦
  • Organizer: 第111回日本眼科学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2007-04-20
• [Presentation] 涙液油層の動態解析. シンポジウム2前眼部画像診断装置の現況 (2007)
  • Author(s): 横井則彦
  • Organizer: 第31回角膜カンファランス・第23回日本角膜移植学会
  • Place of Presentation: 宮崎
  • Year and Date: 2007-02-11
• [Presentation] 関法による涙液油層伸展動態の自動解析法の開発とその臨床応用 (2007)
  • Author(s): 横井則彦、山田英明、木下 茂、横井則彦、加藤孝久、水草豊.
  • Organizer: 第31回角膜カンファランス・第23回日本角膜移植学会
  • Place of Presentation: 宮崎
  • Year and Date: 2007-02-09
• [Book] 年齢とともにドライアイがひどくなると聞きました. 何か気をつけられることはありますか? 患者さんから浴びせられる眼科疾患100の質問 (2008)
  • Author(s): 横井則彦
• [Book] ドライアイで防腐剤抜きの目薬を使うようにいわれました. どこで手に入るのでしょうか? 患者さんから浴びせられる眼科疾患100の質問 (2008)
  • Author(s): 横井則彦
• [Book] 涙液検査. 今日の眼疾患治療指針第2版 (2007)
  • Author(s): 横井則彦
• [Book] メニスコメトリ、インターフェロメトリ. 今日の眼疾患治療指針 第2版 (2007)
  • Author(s): 横井則彦
• [Book] ドライアイ. 眼科プラクティス18前眼部アトラスIII. 角膜7. 角膜上皮・表面 (2007)
  • Author(s): 横井則彦
• [Book] 眼科プラクティス18 前眼部アトラス (ドライアイの項担当) (2007)
  • Author(s): 横井則彦
  • Total Pages: 6
  • Publisher: 文光堂
• [Book] マイボメトリ、マイボグラフィ. 今日の眼疾患治療指針第2版
  • Author(s): 横井則彦