Roles of oxidative stress in metabolic regulations(Fostering Joint International Research)

• Project/Area Number: 16KK0195
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Uruno Akira 東北大学, 東北メディカル・メガバンク機構, 准教授 (90396474)
• Project Period (FY): 2017 – 2019
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥14,950,000 (Direct Cost: ¥11,500,000、Indirect Cost: ¥3,450,000)
• Keywords: 酸化ストレス / 代謝制御 / Nrf1 / Nrf2 / skn-1 / 線虫 / C. elegans / CNC因子

Outline of Final Research Achievements

Diabetes causes serious complications,　and it is strongly associated with oxidative stress. Transcription factors Nrf2 and Nrf1 belonging to the CNC factor family are known as transcription factors related to oxidative stress, and they also regulate the expression of metabolic genes in addition to antioxidant enzymes, detoxifying metabolic enzymes, proteasome subunits. Since metabolic analysis of Nrf1-deficient mice is technically difficult, nematodes orthologue skn-1 in Nrf1 and Nrf2 was focused on . Knockdown of skn-1 by RNAi and metabolic analysis of skn-1a deficient model were performed. These had different lipid compositions. Furthermore, analysis of the motor ability revealed that it changed.

Academic Significance and Societal Importance of the Research Achievements

糖尿病は患者数は増加しており、その病態の解明は重要な課題である。高濃度グルコースは酸化ストレスを発生させることから、糖尿病は酸化ストレスと関連が強い疾患と考えられているが、酸化ストレスと代謝制御の関連は十分には解明されていない。本研究では、酸化ストレスに関するCNC因子ファミリー転写因子であるskn-1による代謝制御を解明することで、酸化ストレスと代謝制御の関連性について明らかにした。

Research Products

• [Int'l Joint Research] ハーバード大学(米国) (2018)
• [Journal Article] Nrf2 Suppresses Oxidative Stress and Inflammation in App Knock-in Alzheimer’s Disease Model Mice. (2020)
  • Author(s): 3)(*Equal contribution) Uruno A*, Matsumaru D*, Ryoke R, Saito R, Kadoguchi S, Saigusa D, Saito T, Saido TC, Kawashima R, Yamamoto M.
  • Journal Title: Mol Cell Biol. Volume: 40 Issue: 6
  • DOI: 10.1128/mcb.00467-19
  • Peer Reviewed
• [Journal Article] Metabolic Basis of Neuronal Vulnerability to Ischemia; An in Vivo Untargeted Metabolomics Approach (2020)
  • Author(s): Rashad S, Saigusa D, Yamazaki T, Matsumoto Y, Tomioka Y, Saito R, Uruno A, Niizuma K, Yamamoto M, Tominaga T.
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 6507-6507
  • DOI: 10.1038/s41598-020-63483-w
  • Peer Reviewed / Open Access
• [Journal Article] Multiple measurements of the urinary sodium-to-potassium ratio strongly related home hypertension: TMM Cohort Study. (2020)
  • Author(s): Kogure M, Hirata T, Nakaya N, Tsuchiya N, Nakamura T, Narita A, Miyagawa K, Koshimizu H, Obara T, Metoki H, Uruno A, Kikuya M, Sugawara J, Kuriyama S, Tsuji I, Kure S, Hozawa A.
  • Journal Title: Hypertens Res Volume: 43 Issue: 1 Pages: 62-71
  • DOI: 10.1038/s41440-019-0335-2
  • Peer Reviewed
• [Journal Article] Reduced Sleep Efficiency, Measured Using an Objective Device, Was Related to an Increased Prevalence of Home Hypertension in Japanese Adults (2020)
  • Author(s): Hirata T, Nakamura T, Kogure M, Tsuchiya N, Narita A, Miyagawa K, Nochioka K, Uruno A, Obara T, Nakaya N, Metoki H, Kikuya M, Sugawara J, Kuriyama S, Tsuji I, Kure S, Hozawa A.
  • Journal Title: Hypertens Res Volume: 43 Issue: 1 Pages: 23-29
  • DOI: 10.1038/s41440-019-0329-0
  • Peer Reviewed
• [Journal Article] Alteration of the lysophosphatidic acid and its precursor lysophosphatidylcholine levels in spinal cord stenosis: A study using a rat cauda equina compression model. (2019)
  • Author(s): Uranbileg B, Ito N, Kurano M, Saigusa D, Saito R, Uruno A, Kano K, Ikeda H, Yamada Y, Sumitani M, Sekiguchi M, Aoki J, Yatomi Y.
  • Journal Title: Scientific reports Volume: 9 Issue: 1 Pages: 16578-16578
  • DOI: 10.1038/s41598-019-52999-5
  • Peer Reviewed / Open Access
• [Journal Article] Conductive Adhesive Film Expands the Utility of Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (2019)
  • Author(s): Saigusa D, Saito R, Kawamoto K, Uruno A, Kano K, Aoki J, Yamamoto M, Kawamoto T.
  • Journal Title: Anal Chem Volume: 91 Issue: 14 Pages: 8979-8986
  • DOI: 10.1021/acs.analchem.9b01159
  • Peer Reviewed / Open Access
• [Journal Article] Identification of celastramycin as a novel therapeutic agent for pulmonary arterial hypertension: high-throughput screening of 5,562 compounds (2019)
  • Author(s): Kurosawa R, Satoh K, Kikuchi N, Kikuchi H, Saigusa D, Elias-Al-Mamun M, Siddique MAH, Omura J, Satoh T, Sunamura S, Nogi M, Numano K, Miyata S, Uruno A, Kano K, Matsumoto Y, Doi T, Aoki J, Oshima Y, Yamamoto M, Shimokawa H
  • Journal Title: Circ Res Volume: 125 Issue: 3 Pages: 309-327
  • DOI: 10.1161/circresaha.119.315229
  • Peer Reviewed / Open Access
• [Journal Article] Nrf2 activation in myeloid cells and endothelial cells differentially mitigates sickle cell disease pathology in mice. (2019)
  • Author(s): Keleku-Lukwete N, Suzuki M, Panda H, Otsuki A, Katsuoka F, Saito R, Saigusa D, Uruno A, Yamamoto M.
  • Journal Title: Blood Adv Volume: 3 Issue: 8 Pages: 1285-1297
  • DOI: 10.1182/bloodadvances.2018017574
  • Peer Reviewed
• [Journal Article] Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals (2019)
  • Author(s): Yamaguchi-Kabata, Y.,（途中略）,Koshiba, S., （途中略）, Tohoku Medical Megabank Project Study Group.（合計１9名、本研究者は５番目）
  • Journal Title: Hum. Genet. Volume: 印刷中 Issue: 4 Pages: 389-409
  • DOI: 10.1007/s00439-019-01998-7
  • Peer Reviewed / Open Access
• [Presentation] The multiple functions of Nrf2 in diabetes mellitus and obesity (2019)
  • Author(s): Uruno A
  • Organizer: The Environmental Response V
  • Int'l Joint Research / Invited
• [Remarks] 東北大学大学院医学系研究科医化学分野
  • URL: http://www.dmbc.med.tohoku.ac.jp/
• [Remarks] Nrf2活性化によるアルツハイマー病改善作用の解明
  • URL: https://www.tohoku.ac.jp/japanese/2020/01/press20200121-02-nrf2.html
• [Patent(Industrial Property Rights)] 生体組織上の還元型グルタチオン分布を測定する方法及び診断用データの取得方法 (2019)
  • Inventor(s): 山本雅之、宇留野晃、三枝大輔、齋藤律水
  • Industrial Property Rights Holder: 山本雅之、宇留野晃、三枝大輔、齋藤律水
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-122085
  • Filing Date: 2019