Analysis of the novel defense mechanism against antigens and infections in the human nasal epihelium

• Project/Area Number: 18K09350
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56050:Otorhinolaryngology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Okuni Tsuyoshi 札幌医科大学, 医学部, 講師 (40464490)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ヒト鼻粘膜上皮 / 上皮バリア / 上気道慢性炎症 / HMBG1 / p63 / ヒト鼻粘膜上皮細胞 / タイト結合 / h TERT / ギャップ結合 / CYP / KLF11

Outline of Final Research Achievements

Transcriptional factor p63 is a member of the p53 family related to the regulation of cell proliferation and apotosis. Although the expression of p63 is increased in chronic airway inflammation such as in patients with allergic rhinitis, its role remains unclear. In the present study, our aim is to elucidate the role and regulation of p63 expression in the human nasal mucosal epithelium.
In the normal human nasal epithelial cells, p63 was associated with the negative adjustment mechanism of the expression of the tight junction and the microvilli. And, HMBG1, which is the transcription factor increasing in blood and nasal discharge of patients with allergic rhinitis, was likely to be association with the expression of p63 and the tight-junction protein LSR via the TGF-beta signaling pathway . In the future, it was suggested that p63 and TGF-beta could be the therapeutic targets for allergic rhinitis

Academic Significance and Societal Importance of the Research Achievements

アレルギー性鼻炎や好酸球性副鼻腔炎といった上気道の難治性慢性炎症性疾患は，本邦のみならず世界的に増加傾向にある。現在，これらの疾患に対する根治的な治療法はなく，新規治療薬の開発が望まれる。
われわれはアレルギー性鼻炎患者で発現亢進する転写因子p63に着目し，正常ヒト鼻粘膜上皮細胞を用いて鼻粘膜におけるp63の役割および発現調節について検討した。
結果p63は鼻粘膜上皮細胞のタイト結合，微絨毛発現に対し抑制的に働いていた。また，転写因子HMBG1は，TGF-βシグナルを介し鼻粘膜上皮バリア機能の低下に関わっていた。将来的に，TGF-β1受容体阻害が上気道慢性炎症の治療に結びつくことが期待された。

Research Products

• [Journal Article] Induction of airway progenitor cells via p63 and KLF11 by Rho-kinase inhibitor Y27632 in hTERT-human nasal epithelial cells. (2019)
  • Author(s): Kaneko Y, Konno T, Kakuki T, Miyata R, Ohkuni T, Kakiuchi A, Yajima R, Ohwada K, Kurose M, Himi T, Takano K, Kojima T.
  • Journal Title: Am J Transl Res Volume: 11 Pages: 599-611
  • Peer Reviewed / Open Access