Analysis of IGF-1 receptor-independent signaling from IGF-1 and its application for drug development

• Project/Area Number: 25670128
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Yamaguchi University
• Principal Investigator: INUI Makoto 山口大学, 医学(系)研究科(研究院), 教授 (70223237)
• Co-Investigator(Kenkyū-buntansha): SAKAI Hiroki 山口大学, 大学院医学系研究科, 助教 (40464367)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 創傷治癒 / 細胞遊走 / インスリン様成長因子 / ペプチド / アンギオテンシン / 皮膚 / アンギオテンシンI変換酵素 / 角膜

Outline of Final Research Achievements

Growth factors including insulin-like growth factor (IGF-1) play important roles in epithelial wound healing. We previously demonstrated that the C domain of IGF-1 as well as a tetrapeptides derived from the C domain, SSSR is responsible for the promotion of keratinocyte migration and cutaneous wound healing by IGF-1. Here we studied the molecular mechanisms of the action of SSSR in keratinocytes. We demonstrated that the promotion of keratinocyte migration by SSSR or IGF-1 did not require the IGF-1 receptor but rather was mediated by signaling from angiotensin II generated by angiotensin I-converting enzyme. Our results provide new insight into the action of IGF-1 in wound healing as well as a foundation for a potential new peptide-based treatment of skin wounds.

Research Products

• [Int'l Joint Research] カンザス州立大学(米国)
• [Int'l Joint Research] イオアニア大学(ギリシャ)
• [Journal Article] Signaling mechanism underlying the promotion of keratinocyte migration by angiotensin II (2015)
  • Author(s): Hiroki Sakai, Kenji Matsuura, Yoshie Tanaka, Takeshi Honda, Teruo Nishida, Makoto Inui
  • Journal Title: Molecular Pharmacology Volume: 87 Issue: 2 Pages: 277-285
  • DOI: 10.1124/mol.114.096461
  • Peer Reviewed
• [Journal Article] Peptide therapies for ocular surface disturbances based on fibronectin-integrin interactions. (2015)
  • Author(s): Nishida, T., Inui, M., and Nomizu, M.
  • Journal Title: Progress in Retinal and Eye Research Volume: 47 Pages: 38-63
  • DOI: 10.1016/j.preteyeres.2015.01.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Involvement of angiotensin II type 2 receptor (AT2R) signaling in human pancreatic ductal adenocarcinoma (PDAC): a novel AT2R agonist effectively attenuates growth of PDAC grafts in mice. (2015)
  • Author(s): Ishiguro S, Yoshimura K, Tsunedomi R, Oka M, Takao S, Inui M, Kawabata A, Wall T, Magafa V, Cordopatis P, Tzakos AG, Tamura M.
  • Journal Title: Cancer Biol Ther. Volume: 16 Issue: 2 Pages: 307-316
  • DOI: 10.1080/15384047.2014.1002357
  • Peer Reviewed / Open Access
• [Journal Article] Expression of B7-H3, a Potential Factor of Tumor Immune (2014)
  • Author(s): Ｎ．Ｍａｅｄａ， Ｋ．Ｙｏｓｈｉｍｕｒａ，Ｓ．Ｙａｍａｍｏｔｏ
  • Journal Title: Ann Surg Oncol Volume: Epub ahead of print Issue: S4 Pages: 546-554
  • DOI: 10.1245/s10434-014-3564-2
  • Peer Reviewed / Open Access
• [Journal Article] A cell-penetrating phospholamban-specific RNA aptamer enhances Ca2+ transients and contractile function in cardiomyocytes. (2014)
  • Author(s): Sakai, H., Ikeda, Y., Honda, T., Tanaka, Y., Shiraishi, K., and Inui, M.
  • Journal Title: J. Mol. Cell. Cardiol. Volume: 76 Pages: 177-185
  • DOI: 10.1016/j.yjmcc.2014.09.006
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regulation of adipocyte differentiation of 3T3-L1 cells by PDZRN3 (2013)
  • Author(s): Honda, T., Ishii, A., and Inui, M
  • Journal Title: Am. J. Physiol. Cell Physiol Volume: 304 Issue: 11 Pages: C1091-C1097
  • DOI: 10.1152/ajpcell.00343.2012
  • Peer Reviewed
• [Presentation] IGF-1 promotes epithelial wound healing independently of the IGF-1 receptor via angiotensin II signaling. (2016)
  • Author(s): 酒井大樹、松浦健二、本田健、西田輝夫、乾 誠
  • Organizer: 第８９回日本薬理学会
  • Place of Presentation: 横浜市（パシフィコ横浜）
  • Year and Date: 2016-03-09
• [Presentation] Regulation of myogenic differentiation by PDZRN3 through modification of Id2 expression (2016)
  • Author(s): 本田健、仲田成美、永井涼人、乾 誠
  • Organizer: 第８９回日本薬理学会
  • Place of Presentation: 横浜市（パシフィコ横浜）
  • Year and Date: 2016-03-09
• [Presentation] 皮膚創傷治癒過程におけるIGH-1と知覚神経由来のサブスタンスPとの協調作用のメカニズム (2015)
  • Author(s): 酒井大樹、松浦健二、本田健、西田輝夫、乾 誠
  • Organizer: 第６８回日本薬理学会西南部会
  • Place of Presentation: 下関市（海峡メッセ下関）
  • Year and Date: 2015-11-21
• [Presentation] スト細胞の走化性におけるトランスグルタミナーゼの役割 (2015)
  • Author(s): 倉増敦朗、武井光、乾 誠
  • Organizer: 第６８回日本薬理学会西南部会
  • Place of Presentation: 下関市（海峡メッセ下関）
  • Year and Date: 2015-11-21
• [Presentation] SEK-1005による血管内皮細胞の遊走及び管腔形成促進効果
  • Author(s): 酒井大樹、中島京、岩田博夫、乾 誠
  • Organizer: 日本循環薬理学会
  • Place of Presentation: 福岡大学（福岡市）
• [Presentation] Promotion of vascular endothelial cell migration and tube formation by SEK-1005.
  • Author(s): 酒井大樹、中島京、岩田博夫、乾 誠
  • Organizer: 日本薬理学会
  • Place of Presentation: 仙台国際センター（仙台市）