Deregulated expression of lncRNAs in cystic fibrosis airway epithelial cells

• Project/Area Number: 16K15163
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Kumamoto University
• Principal Investigator: Shuto Tsuyoshi 熊本大学, 大学院生命科学研究部(薬), 准教授 (80333524)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: マイクロアレイ / CFTR / IncRNA / 薬物輸送担体 / ABCトランスポーター / lncRNA

Outline of Final Research Achievements

Cystic fibrosis (CF) is the lethal inherited disorder caused by mutation in the gene encoding the CF transmembrane regulator (CFTR). However, the molecular basis of what and how gene transcription is regulated by mutant CFTR is still unclear. Here, I focused on lncRNAs, the novel class of functional RNA molecules with little or no protein-coding capacity. Human transcriptome array (HTA) characterized many coding and non-coding RNAs that are dysregulated in CFTR-dysfunctional CF cell line (CFBE41o-), and some of these genes are associated with some of the CF phenotypes. Among these non-coding RNAs, I identified six novel lncRNAs whose expression levels were inversely correlated with that of WT-CFTR, and five of six lncRNAs were significantly and consistently increased in primary human CF airway epithelial cells (DHBE-CF). This study may provide a novel molecular basis for CF-associated gene/protein dysregulation and pathology.

Research Products

• [Journal Article] A split-luciferase-based trimer formation assay as a high-throughput screening platform for therapeutics in Alport syndrome (2018)
  • Author(s): Kohei Omachi, Misato Kamura, Keisuke Teramoto, Haruka Kojima, Tsubasa Yokota, Shota Kaseda, Jun Kuwazuru, Ryosuke Fukuda, Kosuke Koyama, Shingo Matsuyama, Keishi Motomura, Tsuyoshi Shuto, Mary Ann Suico and Hirofumi Kai.
  • Journal Title: Cell Chem Biol. Volume: 印刷中 Issue: 5 Pages: 634-643.e4
  • DOI: 10.1016/j.chembiol.2018.02.003
  • Peer Reviewed
• [Journal Article] Zinc Deficiency via a Splice Switch in Zinc Importer ZIP2/SLC39A2 Causes Cystic Fibrosis-Associated MUC5AC Hypersecretion in Airway Epithelial Cells (2018)
  • Author(s): Kamei S, Fujikawa H, Nohara H, Ueno-Shuto K, Maruta K, Nakashima R, Kawakami T, Matsumoto C, Sakaguchi Y, Ono T, Suico MA, Boucher RC, Gruenert DC, Takeo T, Nakagata N, Li JD, Kai H, Shuto T.
  • Journal Title: EBioMedicine. Volume: 27 Pages: 304-316
  • DOI: 10.1016/j.ebiom.2017.12.025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases. (2016)
  • Author(s): Shuto T, Kamei S, Nohara H, Fujikawa H, Tasaki Y, Sugahara T, Ono T, Matsumoto C, Sakaguchi Y, Maruta K, Nakashima R, Kawakami T, Suico MA, Kondo Y, Ishigami A, Takeo T, Tanaka KI, Watanabe H, Nakagata N, Uchimura K, Kitamura K, Li JD, Kai H.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 39305-39305
  • DOI: 10.1038/srep39305
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The ETS Factor Myeloid Elf-1-Like Factor (MEF)/Elf4 Is Transcriptionally and Functionally Activated by Hypoxia (2016)
  • Author(s): Suico MA, Taura M, Kudo E, Gotoh K, Shuto T, Okada S, Kai H.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 39 Issue: 4 Pages: 641-647
  • DOI: 10.1248/bpb.b15-00796
  • NAID: 130005141679
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Presentation] 気道上皮細胞における亜鉛取り込み輸送体ZIP2の新規スプライススイッチが閉塞製肺疾患の肺病態を調節する (2017)
  • Author(s): 首藤 剛, 亀井 竣輔, 首藤 恵子, Mary Ann Suico, 甲斐 広文
  • Organizer: 第９４回日本生理学会大会
  • Place of Presentation: アクトシティ浜松（静岡）
  • Year and Date: 2017-03-28
  • Invited
• [Presentation] 嚢胞性線維症の気道上皮細胞におけるIncRNAによる自然免疫受容体TLR2の遺伝子発現制御 (2017)
  • Author(s): 丸田 かすみ, 亀井 竣輔, 野原 寛文, 藤川 春花, 中嶋 竜之介, 田崎 幸裕, 首藤 恵子, Mary Ann Suico, 甲斐 広文, 首藤 剛
  • Organizer: 第９０回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール（長崎）
  • Year and Date: 2017-03-15
• [Presentation] 嚢胞性繊維症気道上皮細胞における炎症抑制性IL-37b-SIGIRR axisの破綻 (2017)
  • Author(s): 首藤 恵子, 亀井 竣輔, 内田 友二, 甲斐 広文, 徳富 直史,首藤 剛
  • Organizer: 第34回日本薬学会九州支部大会
• [Presentation] 上皮型Na＋チャネル過剰発現気道上皮細胞の分子生物学的表現型解析：嚢胞性線維症・COPDのモデル細胞となりうるか？ (2017)
  • Author(s): 亀井 竣輔、野原 寛文、川上 太聖、松本 千鶴、坂口 由起、首藤 恵子、Mary Ann Suico、甲斐 広文、首藤 剛
  • Organizer: 第12回トランスポーター研究会年会
• [Presentation] LNC-SOX4-2:1 LINKS CFTR DYSREGULATION AND TLR2 UP-REGULATION IN AIRWAY EPITHELIAL CELLS (2017)
  • Author(s): Shunsuke Kamei, Kasumi Maruta, Hirofumi Nohara, Haruka Fujikawa, Ryunosuke Nakashima, Keiko Ueno-Shuto, Yukihiro Tasaki, Mary Ann Suico, Dieter C. Gruenert, Hirofumi Kai, Tsuyoshi Shuto
  • Organizer: 31st Annual North American Cystic Fibrosis Conference
  • Int'l Joint Research
• [Presentation] CFTR機能破綻に伴い発現変動するlncRNAによる炎症・自然免疫関連受容体TLR2の遺伝子発現制御 (2016)
  • Author(s): 丸田 かすみ, 亀井 竣輔, 野原 寛文, 藤川 春花, 田崎 幸裕, 首藤 恵子, Mary Ann Suico, 甲斐 広文, 首藤 剛
  • Organizer: 第３３回日本薬学会九州支部大会
  • Place of Presentation: 鹿児島大学 郡元キャンパス（鹿児島）
  • Year and Date: 2016-12-03
• [Presentation] A novel splicing switch of zinc importer ZIP2 in airway epithelial cells that controls the mucus hypersecretory and inflammatory phenotypes of obstructive lung diseases (2016)
  • Author(s): 亀井 竣輔, 首藤 恵子, 藤川 春花, 丸田 かすみ, 野原 寛文, 中嶋 竜之介, 松本 千鶴, 坂口 由起, Mary Ann Suico, Dieter C. Gruenert, 甲斐 広文, 首藤 剛
  • Organizer: 第３９回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2016-11-30
• [Presentation] 疾患関連トランスポーター・チャネルの機能・局在調節とその破綻による病態発症機構の解明 (2016)
  • Author(s): 首藤 剛
  • Organizer: 生体機能と創薬シンポジウム2016
  • Place of Presentation: 東北大学 川内キャンパス（宮城）
  • Year and Date: 2016-08-25
  • Invited
• [Presentation] 閉塞性肺疾患における亜鉛トランスポーターの発現制御 (2016)
  • Author(s): 首藤 剛
  • Organizer: 第27回日本微量元素学会学術集会
  • Place of Presentation: 京都大学医学部創立百周年記念施設 芝蘭会館（京都）
  • Year and Date: 2016-07-30
  • Invited
• [Presentation] Pharmacological and genetic approaches determine protease and oxidative stress as exacerbating factors in a mouse model of obstructive lung diseases (2016)
  • Author(s): Tsuyoshi Shuto
  • Organizer: 3rd International Conference on Chronic Obstructive Pulmonary Disease 2016
  • Place of Presentation: Brisbane, Australia
  • Year and Date: 2016-07-11
  • Int'l Joint Research / Invited
• [Presentation] 嚢胞性線維症の気道上皮における機能未知 lncRNA の発現変動 (2016)
  • Author(s): 丸田 かすみ,亀井 竣輔,首藤 剛,野原 寛文,藤川 春花,中嶋 竜之介,田崎 幸裕,首藤 恵子,Mary Ann Suico,甲斐 広文
  • Organizer: 第11回トランスポーター研究会年会
  • Place of Presentation: 京都大学宇治キャンパスきはだホール（京都）
  • Year and Date: 2016-07-02
• [Presentation] 嚢胞性線維症気道上皮細胞における炎症抑制性IL-37b-SIGIRR axisの破綻 (2016)
  • Author(s): 首藤恵子, 亀井 竣輔, 内田 友二, 甲斐 広文, 徳冨 直史, 首藤 剛
  • Organizer: 第６９回日本薬理学会西南部会
  • Place of Presentation: 松山大学（愛媛）
• [Remarks] 熊本大学大学院薬学教育部 遺伝子機能応用学研究室
  • URL: http://molmed730.org/index.html