Dysregulated cell death-associated human disorders

• Project Area: Homeostatic Regulation by Various Types of Cell Death
• Project/Area Number: 26110008
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokushima
• Principal Investigator: YASUTOMO Koji 徳島大学, 大学院医歯薬学研究部(医学域), 教授 (30333511)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥92,300,000 (Direct Cost: ¥71,000,000、Indirect Cost: ¥21,300,000); Fiscal Year 2018: ¥23,660,000 (Direct Cost: ¥18,200,000、Indirect Cost: ¥5,460,000); Fiscal Year 2017: ¥23,660,000 (Direct Cost: ¥18,200,000、Indirect Cost: ¥5,460,000); Fiscal Year 2016: ¥14,170,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥3,270,000); Fiscal Year 2015: ¥14,170,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥3,270,000); Fiscal Year 2014: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000)
• Keywords: 慢性炎症 / 遺伝学 / 肺線維症 / 蕁麻疹 / 細胞死 / 遺伝性疾患 / パイロプトーシス / ネクロプトーシス / ゲノム解析 / 炎症 / 遺伝病 / エクソーム / NLRC4 / サイトカイン / 免疫疾患 / 免疫異常

Outline of Final Research Achievements

We have identified the mutation in NLRC4 as the causative mutation of familial cold autoinflammatory syndorome. The mutation increased the pyroptosis of cells, which is associated with the increased cytokine secretion leading to the inflammation. We also identified the causative gene of familial pulmonary fibrosis and the mutation increased the cell death of type 2 alveolar epithelial cells. The Notch signaling controls the expression of Atp8a2 that has flippase activity. The Notch-mediated expression of Atp8a2 helps the escape of intraepithelial lymphocytes in the small intestine from the engulfment of macrophages.

Academic Significance and Societal Importance of the Research Achievements

細胞死の機能異常が関わる遺伝性疾患の原因遺伝子を同定することに成功し、その解析から各種の細胞死の機能異常が重篤な炎症病態を引き起こしうることが明らかになった。その成果から、重篤な炎症性疾患の治療標的として細胞死の分子経路が該当すると考えられ、今回の研究成果は創薬開発にとって極めて重要な知見をもたらしたと考えられる。

Research Products

• [Journal Article] Notch Balances Th17 and Induced Regulatory T Cell Functions in Dendritic Cells by RegulatingAldh1a2Expression (2017)
  • Author(s): Zaman Taskia Sultana、Arimochi Hideki、Maruyama Satoshi、Ishifune Chieko、Tsukumo Shin-ichi、Kitamura Akiko、Yasutomo Koji
  • Journal Title: The Journal of Immunology Volume: 199 Issue: 6 Pages: 1989-1997
  • DOI: 10.4049/jimmunol.1700645
  • Peer Reviewed
• [Journal Article] Differentiation of preadipocytes and mature adipocytes requires PSMB8 (2016)
  • Author(s): Arimochi H, Sasaki Y, Kitamura A, Yasutomo K.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 26791-26791
  • DOI: 10.1038/srep26791
  • NAID: 120006534960
  • Peer Reviewed / Open Access
• [Journal Article] Notch controls the persistence of autoimmune memory CD4+ T cells by maintaining glucose uptake. (2015)
  • Author(s): Maekawa Y, Ishifune C, Tsukumo S, Hozumi K, Yagita H, Yasutomo K.
  • Journal Title: Nature Medicine Volume: 21 Issue: 1 Pages: 55-61
  • DOI: 10.1038/nm.3758
  • Peer Reviewed