The role of nuclear receptors PXR/CAR in the pathogenesis of inflammatory bowel diseases.

• Project/Area Number: 25460941
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Gunma University
• Principal Investigator: Kakizaki Satoru 群馬大学, 大学院医学系研究科, 講師 (80344935)
• Co-Investigator(Kenkyū-buntansha): 山崎 勇一 群馬大学, 医学部附属病院, 助教 (00582404) ; 堀口 昇男 群馬大学, 医学部附属病院, 助教 (10550022)
• Co-Investigator(Renkei-kenkyūsha): YOSHINARI Kouichi 静岡県立大学, 大学院薬学系研究科, 教授 (60343399)
• Research Collaborator: TAKIZAWA Daichi 群馬大学, 大学院医学系研究科, 大学院生 ; TOJIMA Hiroki 群馬大学, 大学院医学系研究科, 大学院生 ; TAHARA Hiroki 群馬大学, 大学院医学系研究科, 大学院生
• Project Period (FY): 2013-04-01 – 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 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 炎症性腸疾患 / 核内レセプター / ＰＸＲ / ＣＡＲ / ＤＳＳ腸炎 / 炎症性サイトカイン / CAR / PXR / DSS腸炎 / 核内受容体

Outline of Final Research Achievements

The aim of this study was to investigate the role of nuclear receptors PXR and CAR in the pathogenesis of inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease. Wild-type, Pxr-null, Car-null, and Pxr/Car-double null mice were treated with a PXR/CAR agonist or vehicle in a dextran sodium sulfate (DSS)-induced IBD model. PXR and CAR ameliorate DSS-induced ulcerative colitis model via inhibiting inflammatory cytokines and apoptosis.PXR and CAR agonists are promising agents for the treatment of IBD.

Research Products

• [Journal Article] Faecal lactoferrin is a useful biomarker for mucosal healing in patients with ulcerative colitis during granulocyte and monocyte adsorptive apheresis therapy. (2016)
  • Author(s): Sagawa T Kakizaki S, Tomizawa T, et al.
  • Journal Title: Colorectal Dis. Volume: 18 Issue: 7 Pages: 696-702
  • DOI: 10.1111/codi.13258
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A prospective randomized controlled trial of AJG522 versus standard PEG+E as bowel preparation for colonoscopy. (2015)
  • Author(s): Sagawa T, Sato K, Tomizawa T, Mizuide M, Yasuoka H, Shimoyama Y, Kuribayashi S, Kakizaki S, Kawamura O, Kusano M, Yamada M.
  • Journal Title: Biomed Res Int. Volume: 2015 Pages: 521746-521746
  • DOI: 10.1155/2015/521756
  • Peer Reviewed
• [Journal Article] Safety and efficacy of balloon-occluded transcatheter arterial chemoembolization using miriplatin for hepatocellular carcinoma. (2014)
  • Author(s): Arai H, Abe T, Takayama H, Toyoda M, Ueno T, Kakizaki S, Sato K.
  • Journal Title: Hepatol Res. Volume: 44 Issue: 6 Pages: 663-666
  • DOI: 10.1111/hepr.12403
  • Peer Reviewed
• [Journal Article] Protection against high-fat diet-induced obesity in Helz2-deficient male mice due to enhanced expression of hepatic leptin receptor (2014)
  • Author(s): Yoshino S, Satoh T, Yamada M, Hashimoto K, Tomaru T, Katano-Toki A, Kakizaki S, Okada S, Shimizu H, Ozawa A, Tuchiya T, Ikota H, Nakazato Y, Mori M, Matozaki T, Sasaki T, Kitamura T, Mori M.
  • Journal Title: Endocrinology. Volume: 155 Issue: 9 Pages: 3459-3472
  • DOI: 10.1210/en.2013-2160
  • Peer Reviewed
• [Journal Article] Expression of amino acid transporters (LAT1, ASCT2 and xCT) as clinical significance in hepatocellular carcinoma. (2014)
  • Author(s): Namikawa M, Kakizaki S, Kaira K, Tojima H, Yamazaki Y, Horiguchi N, Sato K, Oriuchi N, Tominaga H, Sunose Y, Nagamori S, Kanai Y, Oyama T, Takeyoshi I, Yamada M.
  • Journal Title: Hepatol Res. Volume: in press Issue: 9 Pages: 1014-1022
  • DOI: 10.1111/hepr.12431
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MK-0626, a selective DPP-4 inhibitor, attenuates hepatic steatosis in ob/ob mice. (2014)
  • Author(s): Ohyama T, Sato K, Yamazaki Y, Hashizume H, Horiguchi N, Kakizaki S, Mori M, Kusano M, Yamada M.
  • Journal Title: World J Gastroenterol Volume: 20 Issue: 43 Pages: 16227-35
  • DOI: 10.3748/wjg.v20.i43.16227
  • Peer Reviewed / Open Access
• [Journal Article] Carbon dioxide insufflation reduces the discomfort due to colonoscopy as objectively analyzed by salivary stress markers. (2013)
  • Author(s): Iida T, Okamura S, Kakizaki S, Sagawa T, Zhang Y, Kobayashi R, Masuo T, Mori M.
  • Journal Title: Acta Gastroenterol Belg. Volume: 76 Pages: 219-224
  • Peer Reviewed
• [Journal Article] Transforming growth factor-α activates pancreatic stellate cells and may be involved in matrix metalloproteinase-1 upregulation. (2013)
  • Author(s): Tahara H, Sato K, Yamazaki Y, Ohyama T, Horiguchi N, Hashizume H, Kakizaki S, Takagi H, Ozaki I, Arai H, Hirato J, Jesenofsky R, Masamune A, Mori M.
  • Journal Title: Lab Invest Volume: 93 Pages: 720-732
  • DOI: 10.1155/2013/458543
  • Peer Reviewed
• [Presentation] 核内レセプターからみた肝疾患「核内レセプターCAR(constitutive androstane receptor)の肝疾患における役割」 (2016)
  • Author(s): 柿崎 暁,山崎勇一,Masahiko Negishi.
  • Organizer: 第52回日本肝臓学会総会 （ワークショップ）
  • Place of Presentation: 千葉市（日本）
  • Year and Date: 2016-05-19
• [Presentation] Development of new therapeutic agents for inflammatory bowel diseases targeting the nuclear receptor CAR/PXR. (2016)
  • Author(s): Kakizaki S, Uehara D, Yamazaki Y, Horiguchi N, Inoue Y.
  • Organizer: GUMI&AMDE 2016(第3回群馬大学医療開発国際シンポジウム, 第８回先端マイクロデバイス工学国際会議）
  • Place of Presentation: 桐生市（日本）
  • Int'l Joint Research
• [Presentation] Fecal lactoferrin is a useful biomarker for mucosal healing in cases of ulcerative colitis during monocyte adsorptive apheresis therapy. (2015)
  • Author(s): Tomizawa T Kakizaki S, Sagawa T, et al.
  • Organizer: APDW2015(アジア太平洋消化器病学会）
  • Place of Presentation: 台北市（台湾）
  • Year and Date: 2015-12-03
  • Int'l Joint Research
• [Presentation] IGFBP1 mediates pregnane X receptor-induced morphological changes and migration of hepatocellular carcinoma cells. (2015)
  • Author(s): Yamazaki Y, Kodama S, Kakizaki S, et al.
  • Organizer: APDW2015(アジア太平洋消化器病学会）
  • Place of Presentation: 台北市（台湾）
  • Year and Date: 2015-12-03
  • Int'l Joint Research
• [Presentation] 肝細胞癌株におけるIGFBP-1を介した核内受容体PXR活性化による形態変化、細胞遊走 (2015)
  • Author(s): 山崎勇一、児玉 進、柿崎 暁、他
  • Organizer: 第57回日本消化器病学会大会
  • Place of Presentation: グランドプリンスホテル新高輪（東京）
  • Year and Date: 2015-10-08