Innovation of novel therapeutics against diabetic nephropathy targeting ChREBP

• Project/Area Number: 16K15492
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Endocrinology
• Research Institution: Tohoku University
• Principal Investigator: Sugawara Akira 東北大学, 医学系研究科, 教授 (90270834)
• Co-Investigator(Renkei-kenkyūsha): SAWATUBASHI Shun 徳島大学, 藤井節郎記念医科学センター, 講師 (70535103) ; TAKEMOTO Tatsuya 徳島大学, 藤井節郎記念医科学センター, 助教 (30443899) ; YAMAMOTO Yasuhiko 金沢大学, 大学院医歯薬保健学総合研究科, 教授 (20313637) ; TAKAGI Kiyoshi 東北大学, 大学院医学系研究科, 助教 (80595562) ; Sato Horoshi 東北大学, 大学院薬学研究科, 教授 (60215829) ; Yokoyama Atsushi 東北大学, 大学院医学系研究科, 助教 (20572332) ; ITO Ryo 東北大学, 大学院医学系研究科, 助教 (80733815) ; DOI Takayuki 東北大学, 大学院薬学研究科, 教授 (90212076)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: CRISPR/Cas9システム / ChREBP / 糖尿病性腎症 / ハイスループットスクリーニング / 化合物ライブラリー / 糖質応答転写因子 / 創薬 / スクリーニング

Outline of Final Research Achievements

1) Generation of ChREBP KO mice. We have succeeded in generating ChREBP KO mice (C57BL/6J) using CRISPR/Cas9 system. 2) Generation of high throughput screening (HTS) system using MES13 ChoRE-Luc cells. We have succeeded in generating HTS system using the cell line by obtaining Z score above 0.5. 3) HTS of Tohoku University chemical library: We obtained 13 hit chemicals among 5,861 compounds. Among them, we selected 1 compound (X) for the further investigation. 4) Administration of chemical compounds to Ins-iNOS-transgenic mice: We are now administrating the compound X to the mice.

Research Products

• [Journal Article] The reduction of heparan sulphate in the glomerular basement membrane does not augment urinary albumin excretion (2018)
  • Author(s): Satoshi Aoki, Akiko Saito-Hakoda, Takeo Yoshikawa, Kyoko Shimizu, Kiyomi Kisu, Susumu Suzuki, Kiyoshi Takagi, Shuji Mizumoto, Shuhei Yamada, Toin H. van Kuppevelt, Atsushi Yokoyama, Taiji Matsusaka, Hiroshi Sato, Sadayoshi Ito, and Akira Sugawara
  • Journal Title: Nephrology Dialysis Transplantation Volume: 33 Issue: 1 Pages: 26-33
  • DOI: 10.1093/ndt/gfx218
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Suppressive effects of RXR agonist PA024 on adrenal CYP11B2 expression, aldosterone secretion and blood pressure (2017)
  • Author(s): Suzuki Dai、Saito-Hakoda Akiko、Ito Ryo、Shimizu Kyoko、Parvin Rehana、Shimada Hiroki、Noro Erika、Suzuki Susumu、Fujiwara Ikuma、Kagechika Hiroyuki、Rainey William E.、Kure Shigeo、Ito Sadayoshi、Yokoyama Atsushi、Sugawara Akira
  • Journal Title: PLoS One Volume: 12 Issue: 8 Pages: e0181055-e0181055
  • DOI: 10.1371/journal.pone.0181055
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High glucose stimulates expression of aldosterone synthase (CYP11B2) and secretion of aldosterone in human adrenal cells (2017)
  • Author(s): Shimada Hiroki、Kogure Naotaka、Noro Erika、Kudo Masataka、Sugawara Kaori、Sato Ikuko、Shimizu Kyoko、Kobayashi Makoto、Suzuki Dai、Parvin Rehana、Saito-Ito Takako、Uruno Akira、Saito-Hakoda Akiko、Rainey William E.、Ito Sadayoshi、Yokoyama Atsushi、Sugawara Akira
  • Journal Title: FEBS Open Bio Volume: 7 Issue: 9 Pages: 1410-1421
  • DOI: 10.1002/2211-5463.12277
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of NeuroD1 on the negative regulation of Pomc expression by glucocorticoid. (2017)
  • Author(s): Parvin R, Saito-Hakoda A, Shimada H, Shimizu K, Noro E, Iwasaki Y, Fujiwara K, Yokoyama A, Sugawara A.
  • Journal Title: PLoS One. Volume: 12(4) Issue: 4 Pages: e0175435-e0175435
  • DOI: 10.1371/journal.pone.0175435
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] MEKT1, a novel PPAR-gamma agonist, significantly suppressed Pomc expression/ACTH secretion in AtT20 cells (2018)
  • Author(s): Rehana Parvin, Akiko Saito-Hakoda, Hiroki Shimada, Erika Noro, Susumu Suzuki, Hiroyuki Miyachi Atsushi Yokoyama, Akira Sugawara
  • Organizer: ENDO2018
  • Int'l Joint Research
• [Presentation] Involvement of IKK complex in the regulation of a glucose-responsive transcriptional factor ChREBP in pancreatic β-cell (2018)
  • Author(s): Erika Noro, Atsushi Yokoyama, Naotaka Kogure, Rina Momma, Kyoko Shimizu, Rehana Parvin, Susumu Suzuki, Hiroki Shimada, Hiroki Shima, Kazuhiko Igarashi, Akira Sugawara
  • Organizer: ENDO2018
  • Int'l Joint Research
• [Presentation] Generation and functional analyses of stable H295R cell lines expressing mutants KCNJ5 proteins (2018)
  • Author(s): Ryo Ito, Ikuko Sato, Keita Hoshi, Akira Sugawara
  • Organizer: ENDO2018
  • Int'l Joint Research
• [Presentation] Possible Involvement of ChREBP in the Progression of Diabetic Kidney Disease in the Renal Tubules (2018)
  • Author(s): Susumu Suzuki, Atsushi Yokoyama, Erika Noro, Satoshi Aoki, Rehana Parvin, Hiroki Shimada, Akira Sugawara
  • Organizer: ISN Frontiers Meeting 2018
  • Int'l Joint Research
• [Presentation] Functional screening of transcriptional co-factors for a glucose-responsive transcriptional factor ChREBP. (2016)
  • Author(s): Erika Noro, Atsushi Yokoyama, Naotaka Kogure, Kyoko Shimizu, Hiroki Shima, Kazuhiko Igarashi, Akira Sugawara
  • Organizer: ENDO2016
  • Place of Presentation: アメリカ合衆国ボストン市
  • Int'l Joint Research
• [Remarks] 東北大学大学院医学系研究科・分子内分泌学分野
  • URL: http://www.med.tohoku.ac.jp/about/laboratory/189.html