Development of novel therapeutic strategies for sickle cell disease by activating Nrf2

• Project/Area Number: 26461395
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Tohoku University
• Principal Investigator: Suzuki Mikiko 東北大学, 医学系研究科, 講師 (80508309)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 鎌状赤血球症 / Nrf2 / 酸化ストレス / Keap1 / NRF2 / KEAP1 / 炎症

Outline of Final Research Achievements

Sickle cell disease (SCD) is an inherited disease caused by a mutation in globin gene. Hemoglobins containing the mutated globin polymerize in red blood cells (RBC) and deform RBC into a sickle-like shape. The sickle-shaped RBCs are prone to intravascular hemolysis and intermittent blood glow occlusion, which results in ischemia-reperfusion injury generating oxidative stresses. Nrf2 is a transcription factor that induces expression of target genes involved in cellular defense against oxidative stresses. In this study, we found that genetic and pharmacologic activation of Nrf2 ameliorated tissue damages and inflammation in SCD model mice, indicating that Nrf2 activation relieves symptoms of SCD. Based on these results, we propose that Nrf2 is a therapeutic target for the treatment of SCD.

Research Products

• [Int'l Joint Research] ミシガン大学(米国)
• [Journal Article] Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation. (2017)
  • Author(s): Tsuchida K, Tsujita T, Hayashi M, Ojima A, Keleku-Lukwete N, Katsuoka F, Otsuki A, Kikuchi H, Oshima Y, Suzuki M, Yamamoto M.
  • Journal Title: Free Radic Biol Med Volume: 103 Pages: 236-247
  • DOI: 10.1016/j.freeradbiomed.2016.12.041
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Overview of redox regulation by Keap1-Nrf2 system in toxicology and cancer. (2016)
  • Author(s): Suzuki M, Otsuki A, Keleku-Lukwete N, Yamamoto M.
  • Journal Title: Curr Opin in Toxicol Volume: 1 Pages: 29-36
  • Peer Reviewed
• [Journal Article] Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection. (2016)
  • Author(s): Otsuki A, Suzuki M, Katsuoka F, Tsuchida K, Suda H, Morita M, Shimizu R, Yamamoto M.
  • Journal Title: Free Radic Biol Med Volume: 91 Pages: 45-57
  • DOI: 10.1016/j.freeradbiomed.2015.12.005
  • Peer Reviewed
• [Journal Article] Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation. (2015)
  • Author(s): Nadine Keleku-Lukwete, Mikiko Suzuki, Akihito Otsuki, Kouhei Tsuchida, Saori Katayama, Makiko Hayashi, Eriko Naganuma, Takashi Moriguchi, Osamu Tanabe, James Douglas Engel, Masue Imaizumi, Masayuki Yamamoto
  • Journal Title: Proc Natl Acad Sci U S A Volume: 112 Issue: 39 Pages: 12169-12174
  • DOI: 10.1073/pnas.1509158112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Progenitor stage-specific activity of a cis-acting double GATA motif for Gata1 gene expression (2015)
  • Author(s): Moriguchi T, Suzuki M, Yu L, Takai J, Ohneda K, and Yamamoto M. “
  • Journal Title: Mol Cell Biol Volume: 35 Issue: 5 Pages: 805-815
  • DOI: 10.1128/mcb.01011-14
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fetal globin gene repressors as drug targets for molecular therapies to treat the β-globinopathies (2014)
  • Author(s): Suzuki M, Yamamoto M, and Engel JD.
  • Journal Title: Mol Cell Biol Volume: 34 Issue: 19 Pages: 3560-3569
  • DOI: 10.1128/mcb.00714-14
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Keap1-Nrf2 System: Potential Role in Prevension of Sickle Cell Disease and Inflammation. (2015)
  • Author(s): Nadine Keleku-Lukwete, Mikiko Suzuki, Akihito Otsuki, Kouhei Tsuchida, Saori Katayama, Makiko Hayashi, Eriko Naganuma, Takashi Moriguchi, Osamu Tanabe, James Douglas Engel, and Masayuki Yamamoto.
  • Organizer: 57th ASH Annual Meeteing
  • Place of Presentation: Orland, FL
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] NRF2 protects sickle cell disease model mice from inflammation and organ damages. (2015)
  • Author(s): Nadine Keleku-Lukwete、鈴木未来子、大槻晃史、土田恒平、片山紗乙莉、林真貴子、森口尚、田邉修、今泉益栄、山本雅之.
  • Organizer: 第81回日本生化学会東北支部例会
  • Place of Presentation: 仙台（東北大学さくらホール）
  • Year and Date: 2015-05-09