Development of novel therapeutics targetingTRP channel for neurotrophic keratopathy

• Project/Area Number: 15K10878
• 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: OKADA YUKA 和歌山県立医科大学, 医学部, 准教授 (50264891)
• Co-Investigator(Kenkyū-buntansha): 雑賀 司珠也 和歌山県立医科大学, 医学部, 教授 (40254544)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 神経麻痺性角膜症 / TRPチャネル / 三叉神経 / 神経麻痺生角膜症 / 角膜 / 創傷治癒

Outline of Final Research Achievements

A mouse model of neurotrophic keratopathy was produced in the cranium by using a needle at the point described above, a bipolar coagulation. Sensory loss was confirmed by the lack of the blink reflex on air jet stimulation as well as by confirming less response with cochet-bonnet aesthesiometer. The cornea of a mouse following electrolysis coagulation of the first branch of the trigeminal nerve showed significant delayed epithelial defect closure. TRPV4 gene introduction into a damaged V1 nerve rescues the impairment of epithelial healing.The system composed of sensory nerve TRPV4 - maintenance of cell stemness - NGFn is one of the major mechanisms of homeostasis of corneal epithelium.

Academic Significance and Societal Importance of the Research Achievements

神経麻痺性角膜症は、三叉神経第１枝領域が障害され角膜知覚が低下することで角膜障害と角膜創傷治癒遅延が惹起される疾患であるが、病態解明が不十分でそれに基づく根治的な治療法はない。角膜保護剤や抗生剤点眼などの対症療法のみできわめて難治性である。
知覚神経麻による神経終末からの神経ペプチドが病態に大きく関与していると想定する中、それらの神経ペプチドの分泌に関与するTRPV4を障害三叉神経で強制発現させることがの神経麻痺性角膜症の治療標的となる可能性を示せた。

Research Products

• [Journal Article] Sensory nerve supports epithelial stem cell function in healing of corneal epithelium in mice: the role of trigeminal nerve transient receptor potential vanilloid 4. (2019)
  • Author(s): Okada Y, Sumioka T, Ichikawa K, Sano H, Nambu A, Kobayashi K, Uchida K, Suzuki Y, Tominaga M, Reinach PS, Hirai SI, Jester JV, Miyajima M, Shirai K, Iwanishi H, Kao WW, Liu CY, Saika S.
  • Journal Title: Lab Invest. Volume: 99(2) Issue: 2 Pages: 210-230
  • DOI: 10.1038/s41374-018-0118-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transient Receptor Potential Channels and Corneal Stromal Inflammation. (2015)
  • Author(s): Okada Y, Reinach PS, Shirai K, Kitano-Izutani A, Miyajima M, Yamanaka O, Sumioka T, Saika S
  • Journal Title: Cornea Volume: 34
  • Peer Reviewed / Open Access / 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 (2018)
  • Author(s): 岡田由香
  • Organizer: 第４２回角膜学会総会
  • Invited
• [Presentation] Effects of loss of TRPV4 function on corneal epithelial wound healing in mice (2016)
  • Author(s): Yuka Okada , Peter S. Reinach , Masayasu Miyajima , Shizuya Saika
  • Organizer: Gordon Research Conference
  • Place of Presentation: Ventura,USA
  • 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、ピーター・ライナック、住岡孝吉、白井久美、山中修、宮嶋正康、雑賀司珠也
  • 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、ピーター・ライナック、白井久美、住岡孝吉、山中修、宮嶋正康、雑賀司珠也
  • Organizer: 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: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: Denver,USA
  • 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、ピーター・ライナック、白井久美、宮嶋正康、雑賀司珠也
  • Organizer: 日本眼科学会
  • Place of Presentation: 札幌
  • Year and Date: 2015-04-16