Cellular and tissue response to hypoxic brain and toxic liver injuries

• Project/Area Number: 17K11581
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: Fukushima Medical University
• Principal Investigator: Iseki Ken 福島県立医科大学, 医学部, 教授 (70332921)
• Co-Investigator(Kenkyū-buntansha): 後藤 薫 山形大学, 医学部, 教授 (30234975)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肝障害 / 肝星細胞 / 線維化 / 四塩化炭素 / PKCδ / 肝星胞線維化 / 脂質代謝酵素 / 放射線障害 / グリオーシス / 低酸素脳症 / 中毒

Outline of Final Research Achievements

We examined how tumor suppressor p53 and TGFbeta signaling pathways are regulated by signal transduction-regulating enzyme diacylglycerol kinase (DGK). In the experiment of whole body ionizing radiation, DGKzeta-KO mice showed robust induction of p53 protein in the spleen and vulnerability at the animal level compared with the wild-type (WT), suggesting a regulatory role of DGKzeta on the p53 pathway. On the other hand, in the experiment of carbon tetrachloride-induced liver injury, DGKalpha-KO mice exhibited an increase in alpha-smooth muscle actin-positive hepatic stellate cells and smad2 phosphorylation level, suggesting enhanced TGFbeta signaling. Collectively, results implicate that DGK family is intimately involved in various pathophysiology of organs.

Academic Significance and Societal Importance of the Research Achievements

交通外傷や心血管障害等による脳障害ならびに中毒性肝障害は、救急診療において日常遭遇する重要症例である。本研究では、これらの病態における組織・細胞レベルの応答メカニズム解明に向けた基礎科学的アプローチを行うものである。物理的な損傷や低酸素障害には、p53が関与する。また中毒性肝障害は、線維化を介した肝硬変の原因となるが、TGFβ経路が重要な役割を果たす。本研究は、申請者らのグループが長年取り組んできた細胞内情報伝達制御因子ジアシルグリセロールキナーゼが、これらの病態制御に関与することを明らかにしたものであり、障害の軽減と回復の促進を目指した臨床応用の一助となる。

Research Products

• [Journal Article] Diacylglycerol kinase α‐selective inhibitors induce apoptosis and reduce viability of melanoma and several other cancer cell lines (2018)
  • Author(s): Yamaki Atsumi、Akiyama Rino、Murakami Chiaki、Takao Saki、Murakami Yuki、Mizuno Satoru、Takahashi Daisuke、Kado Sayaka、Taketomi Akinobu、Shirai Yasuhito、Goto Kaoru、Sakane Fumio
  • Journal Title: Journal of Cellular Biochemistry Volume: 120 Issue: 6 Pages: 10043-10056
  • DOI: 10.1002/jcb.28288
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] DGKζ ablation engenders upregulation of p53 level in the spleen upon whole-body (2018)
  • Author(s): Tanaka T, Iseki K, Tanaka K, Nakano T, Iino M, Goto K
  • Journal Title: Adv Biol Regul. Volume: 67 Pages: 93-100
  • DOI: 10.1016/j.jbior.2017.09.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ε型ジアシルグリセロールキナーゼ欠損は皮下脂肪における褐色化を促進する (2019)
  • Author(s): 中野 知之、後藤 薫
  • Organizer: 第125回日本解剖学会総会
• [Presentation] Diacylglycerol kinase α negatively regulates the activation of myofibroblasts in mouse liver. (2018)
  • Author(s): Tomoyuki Nakano, Keiko Seino, Ken Iseki, Kaoru Goto
  • Organizer: American Society of Cell Biology Meeting
  • Int'l Joint Research