Identification of urothelial master transcription factors diminished in interstitial cystitis

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K11059
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Dokkyo Medical University
• Principal Investigator: Yamanishi Tomonori 獨協医科大学, 医学部, 教授 (90220425)
• Co-Investigator(Kenkyū-buntansha): 加賀 勘家 獨協医科大学, 医学部, 助教 (80584812) ; 井上 健一 獨協医科大学, 医学部, 准教授 (90587974)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: 間質性膀胱炎 / マスター転写因子 / ハンナ型・非ハンナ型 / 主成分分析 / パイオニア因子 / リプログラミング

Outline of Final Research Achievements

To comprehensively grasp the transcription factors (TFs) highly expressed in urothelial cellls, we compared expression profiles between epithelial type and mesenchymal type bladder cancer cell lines by microarray. 82 TFs were newly discovered which had super enhancers in their genomic loci. We measured the expression level of each TF in bladder specimens from Hunner-type (23 cases) and non-Hunner-type (11 cases) interstitial cystitis (IC) patients. Principal component analysis (PCA) classified the 81 TFs into five groups. Notably, specimens from Hunner's and non-Hunner's types were clearly segregated among PC2-4 plane, suggesting that TFs of PC2 and 4 are deregulated in IC patients. Those PCs included the known progenitor markers and pioneer TFs which are critical for direct reprogramming. Subsequently we constructed expression vector of those TFs and are performing gain-of-function experiments.

Free Research Field

泌尿器科学

Academic Significance and Societal Importance of the Research Achievements

難病指定された間質性膀胱炎は原因不明で根治手段がない。ハンナ型・非ハンナ型に分類される2つの病型についても、簡便な診断マーカーが存在しない。我々は特定の転写因子群がハンナ型・非ハンナ型の患者生検で発現量が異なることを発見した。この意義は、2つの病型の診断マーカーが得られたことに留まらない。転写因子を特定の組み合わせで強制発現すると、細胞の運命を転換させる現象が知られている(例：iPS細胞)。今回同定した転写因子を複数組み合わせて、膀胱上皮の前駆細胞を人工的に作成する技術開発に取り組んでいる。これが成功すれば、前駆細胞を移植するかもしくは遺伝子治療によって、間質性膀胱炎を根治できると期待する。