New treatment strategy for ocular fibrotic diseases by modulation of TGFbeta signal with TRP cation channnels

• Project/Area Number: 25462729
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Wakayama Medical University
• Principal Investigator: Saika Shizuya 和歌山県立医科大学, 医学部, 教授 (40254544)
• Co-Investigator(Kenkyū-buntansha): 住岡 孝吉 和歌山県立医科大学, 医学部, 講師 (40433362) ; 山中 修 和歌山県立医科大学, 医学部, 博士研究員 (50254545) ; 岡田 由香 和歌山県立医科大学, 医学部, 准教授 (50264891)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 組織瘢痕化 / 成長因子 / TRPイオンチャネル / 角膜 / 眼 / ノックアウトマウス / 細胞培養 / 水晶体 / TRPV4 / TRPA1 / イオンチャンネル / 創傷治癒 / 線維化 / シグナル / TRPチャネル / TGFβシグナル / Smad / MAPキナーゼ / 線維芽細胞 / 炎症 / 瘢痕

Outline of Final Research Achievements

Tissue fibrosis induced by an alkali exposure was effectively suppressed by TRP channel (TRPA1, TRPV1, TRPV4)-signals modulation of TGFbeta-MAPK/Smad signals in genetically modified mouse lines. The inhibitory effects was reproduced by specific chemical inhibitors of each channel. TRPV4 signal was also found to be related to interleukin-6 signal in tissue fibrosis. A similar mechanism might be invilved in conjunctival fibrosis, although we have preliminary data. Tissue fibrosis in a mouse lens related to epithelial-mesenchymal transition did not seem to be related to TRP cation channel signals.

Research Products

• [Journal Article] Bacteriology of the conjunctiva in pre-cataract surgery patients with occluded nasolacrimal ducts and the operation outcomes in Japanese patients. (2017)
  • Author(s): Hayashi Y, Miyamoto T, Fujita S, Tomoyose K, Ishikawa N, Kokado M, Sumioka T, Okada Y, Saika S.
  • Journal Title: BMC Ophthalmol. Volume: 17 Issue: 1 Pages: 15-15
  • DOI: 10.1186/s12886-017-0410-x
  • Peer Reviewed / Open Access
• [Journal Article] Loss of TRPV4 Function Suppresses Inflammatory Fibrosis Induced by Alkali-Burning Mouse Corneas. (2016)
  • Author(s): Okada Y, Shirai K, Miyajima M, Reinach PS, Yamanaka O, Sumioka T, Kokado M, Tomoyose K, Saika S.
  • Journal Title: PLoS One Volume: 11 Issue: 12 Pages: e0167200-e0167200
  • DOI: 10.1371/journal.pone.0167200
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of epiplakin-knockdown in cultured corneal epithelial cells. (2016)
  • Author(s): Kokado M, Okada Y, Miyamoto T, Yamanaka O, Saika S.
  • Journal Title: BMC Res Notes. Volume: 9 Issue: 1 Pages: 278-278
  • DOI: 10.1186/s13104-016-2082-7
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A Case of Solitary Nonvascularized Corneal Epithelial Dysplasia. (2016)
  • Author(s): Morii T, Sumioka T, Izutani-Kitano A, Takada Y, Okada Y, Kao WW, Saika S.
  • Journal Title: Case Rep Ophthalmol Med. Volume: 5687285 Pages: 5687285-5687285
  • DOI: 10.1155/2016/5687285
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Inhibition of development of laser-induced choroidal neovascularization with suppression of infiltration of macrophages in Smad3-null mice. (2016)
  • Author(s): Iwanishi H, Fujita N, Tomoyose K, Okada Y, Yamanaka O, Flanders KC, Saika S.
  • Journal Title: Lab Invest. Volume: e-journal Issue: 6 Pages: 641-51
  • DOI: 10.1038/labinvest.2016.30
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transient Receptor Potential Channels and Corneal Stromal Inflammation. (2015)
  • Author(s): 0kada Y,Reinach PS,Shirai K,Kitano-Izutani A,Miyajima M,Yamanaka O,Sumioka T, Saika S
  • Journal Title: Cornea Volume: Suppl 11 Issue: Supplement 11 Pages: 136-41
  • DOI: 10.1097/ico.0000000000000602
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ocular transient receptor potential channel function in health and disease. (2015)
  • Author(s): Reinach PS, Mergler S, Okada Y, Saika S.
  • Journal Title: BMC Ophthalmol. Volume: Suppl 1 Issue: S1 Pages: 153-153
  • DOI: 10.1186/s12886-015-0135-7
  • Peer Reviewed / Open Access
• [Journal Article] Suppression of In Vivo Neovascularization by the Loss of TRPV1 in Mouse Cornea. (2015)
  • Author(s): Tomoyose K, Okada Y, Sumioka T, Miyajima M, Flanders KC, Shirai K, Morii T, Reinach PS, Yamanaka O, Saika S.
  • Journal Title: J Ophthalmol. Volume: Sep 27 Pages: 706404-706404
  • DOI: 10.1155/2015/706404
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Temperature-sensitive transient receptor potential channels in corneal tissue layers and cells. (2014)
  • Author(s): Mergler S1, Valtink M, Takayoshi S, Okada Y, Miyajima M, Saika S, Reinach PS.
  • Journal Title: Ophthalmic Res. Volume: 52 Issue: 3 Pages: 151-159
  • DOI: 10.1159/000365334
  • Peer Reviewed / Open Access
• [Journal Article] TRPA1 is required for TGF-β signaling and its loss blocks inflammatory fibrosis in mouse corneal stroma. (2014)
  • Author(s): 2．Okada Y, Shirai K, Reinach PS, Kitano-Izutani A, Miyajima M, Flanders KC, Jester JV, Tominaga M,Saika S
  • Journal Title: Lab Invest. Volume: 94(9) Pages: 1030-41
  • Peer Reviewed / Open Access
• [Journal Article] Impairment of corneal epithelial wound healing in a TRPV1-deficient mouse. (2014)
  • Author(s): 4．Sumioka T, Okada Y, Reinach PS, Shirai K, Miyajima M, Yamanaka O, Saika S:
  • Journal Title: Vis Sci. Volume: 55(5) Pages: 3295-302
  • Peer Reviewed / Open Access
• [Journal Article] Errors in the prediction of postoperative refraction following intraocular lens implantation in eyes with pseudoexfoliation syndrome (2013)
  • Author(s): Ishikawa N, Hayashi Y, Miyamoto T, Saika S
  • Journal Title: J Cataract Refract Surg Volume: 39(4) Issue: 4 Pages: 649-650
  • DOI: 10.1016/j.jcrs.2013.02.023
  • Peer Reviewed
• [Journal Article] Increased fragility, impaired differentiation, and acceleration of migration of corneal epithelium of epiplakin-null mice. (2013)
  • Author(s): Kokado M, Okada Y, Goto M, Ishikawa K, Miyamoto T, Yamanaka O, Fujiwara S, Saika S
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 54 Issue: 5 Pages: 3780-9
  • DOI: 10.1167/iovs.12-11077
  • Peer Reviewed
• [Presentation] 網膜静脈分枝閉塞症に伴う黄斑浮腫に対する抗VEGF治療前後のM-CHARTSを用いた変視評価 (2016)
  • Author(s): 住岡孝吉、岩西宏樹、二出川裕香、森井智也、雑賀司珠也
  • Organizer: 第70回日本臨床眼科学会
  • Place of Presentation: 京都
  • Year and Date: 2016-11-03
• [Presentation] マウス角膜創傷治癒過程におけるマトリセルラータンパク質の役割 (2016)
  • Author(s): 住岡孝吉、山中 修、岡田由香、雑賀司珠也
  • Organizer: 第48回日本結合組織学会
  • Place of Presentation: 長崎
  • Year and Date: 2016-06-04
• [Presentation] Effects of loss of TRPV4 function on corneal epithelial wound healing in mice. (2016)
  • Author(s): Okada Y, Reinach PS, Miyajima M, Saika S.
  • Organizer: he Association for Research in Vision and Ophthalmology Annual Meeting
  • Place of Presentation: Seatle
  • Year and Date: 2016-05-01
  • Int'l Joint Research
• [Presentation] Relation of Tenascin X and VEGF in the corneal cauterization model (2016)
  • Author(s): Sumioka T, Okada Y, Yamanaka O, Nidegawa Y, Miyajima M, Matsumoto K, Saika S
  • Organizer: The Association for Research in Vision and Ophthalmology Annual Meeting
  • Place of Presentation: Seatle
  • Year and Date: 2016-05-01
  • Int'l Joint Research
• [Presentation] マウス神経麻痺性角膜症モデルに対する三叉神経節でのTRPV4強制発現による治療効果 (2016)
  • Author(s): 岡田由香、佐野裕美、小林憲太、富永真琴、南部敦、雑賀司珠也
  • Organizer: 第120回日本眼科学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2016-04-08
• [Presentation] 角膜電熱凝固モデルにおけるテネイシンXとVEGFの関連 (2016)
  • Author(s): 住岡孝吉、岡田由香、山中 修、二出川裕香、宮嶋正康、松本健一、雑賀司珠也
  • Organizer: 第120回日本眼科学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2016-04-08
• [Presentation] Effects of loss of TRPV4 function on corneal epithelial wound healing in mice (2016)
  • Author(s): Yuka Okada1 , Peter S. Reinach2 , Masayasu Miyajima3 , Shizuya Saika1
  • Organizer: Gordon Research Conferences
  • Place of Presentation: カリフォルニア, アメリカ
  • Year and Date: 2016-02-28
  • Int'l Joint Research
• [Presentation] TRPV4イオンチャネルの角膜上皮欠損の創傷治癒での役割 (2016)
  • Author(s): 岡田由香1、ピーター・ライナック2、住岡孝吉1、白井久美1、山中修1、宮嶋正康3、雑賀司珠也1
  • Organizer: 角膜カンファランス
  • Place of Presentation: 軽井沢
  • Year and Date: 2016-02-18
• [Presentation] TRPA1イオンチャネルの角膜上皮欠損の創傷治癒での役割 (2015)
  • Author(s): 岡田由香1、ピーター・ライナック2、白井久美1、住岡孝吉1、山中修1、宮嶋正康3、雑賀司珠也1
  • Organizer: 第19t回眼創傷治癒研究会
  • Place of Presentation: 姫路
  • Year and Date: 2015-08-22
• [Presentation] Impairment of cornea epithelium wound healing in a TRPA1-deficient mouse (2015)
  • Author(s): Yuka Okada, Kumi Shirai, Peter Reinach, Masayasu Miyajima, Shizuya Saika
  • Organizer: Association for Research in Vision and Ophthalmology (ARVO) 2015 Annual Meeting
  • Place of Presentation: コロラド,アメリカ
  • Year and Date: 2015-05-03
  • Int'l Joint Research
• [Presentation] 細胞膜TRPA1イオンチャネルの角膜上皮欠損の創傷治癒での役割 (2015)
  • Author(s): 岡田由香1、ピーター・ライナック2、白井久美1、宮嶋正康3、雑賀司珠
  • Organizer: 第119回日本眼科学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2015-04-14
• [Presentation] Roles of matricellular proteins in EMT of lens epithelium. (2014)
  • Author(s): Saika S:
  • Organizer: The Catholic University of Korea講演会
  • Place of Presentation: Korea
  • Year and Date: 2014-08-25
  • Invited
• [Presentation] Roles of TRP channels in Smad signal and myofibroblast formation in stromal repair (2014)
  • Author(s): Saika S:
  • Organizer: Biennial Meeting of the International Society for Eye Research,
  • Place of Presentation: San Francisco, CA
  • Year and Date: 2014-07-21 – 2014-07-23
  • Invited
• [Presentation] Lacking Smad3 attenuates development of Argon laser-induced CNV in mice (2014)
  • Author(s): Iwanishi H, Sumioka T, Okada Y, Yamanaka O, Saika S
  • Organizer: ARVO
  • Place of Presentation: Orlando, FL
  • Year and Date: 2014-05-04 – 2014-05-08
• [Presentation] Immunohistochemical observation of meibomian gland following ocular surface alkali burning in wild-type and Smad3-deficient mice (2014)
  • Author(s): Mizoguchi S, Okada Y, Arita R, Saika S
  • Organizer: ARVO
  • Place of Presentation: Orlando, FL
  • Year and Date: 2014-05-04 – 2014-05-08
• [Presentation] Effects of β-catenin inhibitor, ICG-001, on cultured human conjunctival fibroblast (2014)
  • Author(s): Yamanaka O, Kao WW, Saika S
  • Organizer: ARVO
  • Place of Presentation: Orlando, FL
  • Year and Date: 2014-05-04 – 2014-05-08
• [Presentation] Impaired angiogenic response in cornea by lacking tenascin X in mice (2014)
  • Author(s): Sumioka T, Okada Y, Nidegawa Y, Miyajima M, Matumoto K, Saika S
  • Organizer: ARVO
  • Place of Presentation: Orlando, FL
  • Year and Date: 2014-05-04 – 2014-05-08
• [Presentation] Role of TRPV1 Ion Chnnel in Corneal Wound Healing
  • Author(s): Shizuya Saika
  • Organizer: GAVIN HERBERT EYE INSTITYTE講演会
  • Place of Presentation: USA
  • Invited
• [Presentation] Modulation of keratocyte-myofibroblast conversion by extracellular matrix in corneal stroma
  • Author(s): Shizuya Saika
  • Organizer: GAVIN HERBERT EYE INSTITYTE講演会
  • Place of Presentation: USA
  • Invited
• [Presentation] Prevention of Keratocyte-Myofibroblast conversion by Targeting Matrix-Cytokine System
  • Author(s): Shizuya Saika
  • Organizer: Annual meeting of the Association for research in Vision and Ophthalmology
  • Place of Presentation: USA
• [Presentation] Loss of Muc16 induces inflammatory reaction in conjunctiva and secondarily affects corneal epithelium and stroma in mice.
  • Author(s): Shizuya Saika
  • Organizer: Gordon Research Conferences
  • Place of Presentation: USA
• [Book] Lens epithelium and posterior capsular opacification (2014)
  • Author(s): Shirai K, Kitano-Izutani A, Miyamoto T, Tanaka S, Saika S
  • Total Pages: 15
  • Publisher: Springer Verlag
• [Book] Lens epithelium and posterior capsular opacification (2014)
  • Author(s): ２．Miyamoto T, Ishikawa N, Shirai K, Kitano-Izutani A, Tanaka S, Saika S
  • Total Pages: 11
  • Publisher: Springer Verlag