Elucidation of regeneration mechanism of digestive tract pacemaker cell by modified TRECK method

• Project/Area Number: 16K15058
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Integrative animal science
• Research Institution: The University of Tokyo
• Principal Investigator: Hori Masatoshi 東京大学, 大学院農学生命科学研究科(農学部), 准教授 (70211547)
• Co-Investigator(Kenkyū-buntansha): 米川 博通 公益財団法人東京都医学総合研究所, 基盤技術研究センター, 特任研究員 (30142110) ; 神沼 修 山梨大学, 大学院総合研究部, 准教授 (80342921)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: カハール介在細胞 / TRECKマウス / c-kit / ANO-1 / ジフテリア毒素 / 消化管 / Cre/loxp / Ano-1 / 獣医学 / 生理学 / 再生医学

Outline of Final Research Achievements

"Interstitial Cells of Cajal (ICC)" controls gastrointestinal motility as pacemaker cells.　In this study, we tried to establish ICC specifically attacked mice using TRECK method, then we investigate gastrointestinal motility dysfunction and GFP-mesenchymal stem cells transplantation in vivo. Finally we aimed to establish the basis of ICC regenerative medicine as a new therapeutic target in gastrointestinal diseases by analyzing the linkage between the process and pacemaker function and gastrointestinal tract transporting ability. Two constructs were constructed by linking the expression regulatory region of about 15-20 kb in the ANO-1 and c-kit genes to the human-derived DT receptor (hDTR) / loxp sequence gene and the Cre recombinase gene, and transgenic (Tg) Mouse was attempted. We are now establishing several transgenic mice, and investigating rate of gene expression.

Research Products

• [Int'l Joint Research] Nevada University, School of Medicine(米国)
• [Journal Article] Disruption of the pacemaker activity of interstitial cells of Cajal via nitric oxide contributes to postoperative ileus (2018)
  • Author(s): Kaji N, Nakayama S, Horiguchi K, Iino S, Ozaki H, Hori M
  • Journal Title: Neurogastroenterol Motil Volume: 15 Issue: 8
  • DOI: 10.1111/nmo.13334
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Micro-coordination of Pacemaker Potentials in the Intestine of the Mouse. (2017)
  • Author(s): Morishita H, Iwata N, Takai C, Mochizuki N, Kaji N, Hori M, Kajioka S, Nakayama S.
  • Journal Title: Gastroenterology Volume: 5085(17) Issue: 8 Pages: 35483-35485
  • DOI: 10.1053/j.gastro.2017.04.016
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Therapeutic Action of Honokiol on Postoperative Ileus via Downregulation of iNOS Gene Expression (2017)
  • Author(s): Mihara T, Mikawa S, Kaji N, Endo M, Oikawa T, Tong-Rong J, Ozaki H, Hori M. Inflammation
  • Journal Title: Inflammation Volume: 40(4) Issue: 4 Pages: 1331-1341
  • DOI: 10.1007/s10753-017-0576-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The 5-HT3 receptor antagonist ondansetron attenuates pancreatic injury in cerulein-induced acute pancreatitis model. (2017)
  • Author(s): Tsukamoto A, Sugimoto T, Onuki Y, Shinoda H, Mihara T, Hori M, Inomata T.
  • Journal Title: Inflammation Volume: 40 Issue: 4 Pages: 1409-1415
  • DOI: 10.1007/s10753-017-0584-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Nitric oxide-induced oxidative stress impairs pacemaker function of murine interstitial cells of Cajal during inflammation (2016)
  • Author(s): Kaji N, Horiguchi K, Iino S, Nakayama S, Ohwada T, Otani Y, Firman, Murata T, Sanders KM, Ozaki H, Hori M
  • Journal Title: Pharmacological Research Volume: 111 Pages: 838-848
  • DOI: 10.1016/j.phrs.2016.07.030
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Epidermal growth factor is a critical regulator of the cytokine IL-33 in intestinal epithelial cells. (2016)
  • Author(s): Islam MS, Horiguchi K, Iino S, Kaji N, Mikawa S, Hori M, Ozaki H.
  • Journal Title: British Journal of Pharmacology Volume: 173 Issue: 16 Pages: 2532-2542
  • DOI: 10.1111/bph.13535
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Neural anti-inflammatory action mediated through two types of ACh receptors of small intestine in POI model mice. For Mosapride citrate. (2017)
  • Author(s): Hori M
  • Organizer: ANMA & JSNM Joint Meeting 2017
  • Place of Presentation: Osaka International Convention Center (OICC) (Osaka・Osaka-city)
  • Year and Date: 2017-03-23
  • Int'l Joint Research
• [Presentation] Neural anti-inflammatory action mediated through two types of ACh receptors of small intestine in POI model mice. For Mosapride citrate. (2017)
  • Author(s): Hori M
  • Organizer: (5th Biennial Congress of the Asian Neurogastroenterology & Motility Association (ANMA)and 19th Japanese Society of Neurogastroenterology and Motility (JSNM)
  • Int'l Joint Research / Invited
• [Presentation] Neural anti-inflammatory action mediated through two types of ACh receptors of small intestine in POI model mice. For Daikenchuto. (2017)
  • Author(s): Hori M
  • Organizer: (5th Biennial Congress of the Asian Neurogastroenterology & Motility Association (ANMA)and 19th Japanese Society of Neurogastroenterology and Motility (JSNM)
  • Int'l Joint Research / Invited
• [Presentation] Neuronal anti-inflammatory signaling via 5-HT4 receptor stimulation in small intestine (2017)
  • Author(s): Kimura H, Imura Y-K, Tsuchida Y, Kaji N, Nakashima J, Mihara T, Mikawa S, Ozaki H, Hori M
  • Organizer: ISAN2017
  • Int'l Joint Research
• [Presentation] マウス結腸輸送能における5-HT3A受容体と5-HT4受容体の機能解析 (2017)
  • Author(s): 長谷川 乃映瑠、三河 翔馬、水野 理介、梶 典幸、尾崎 博、堀 正敏
  • Organizer: 第59回日本平滑筋学会
• [Presentation] 5-フルオロウラシルによる腸管上皮細胞のアポトーシスはセロトニン3A受容体シグナルを介して増強される (2017)
  • Author(s): 三河 翔馬、梶 典幸、三原 大輝、尾崎 博、堀 正敏
  • Organizer: 第137回日本薬理学会関東部会
• [Presentation] Th1/Th2/Th17シグナルと腸管運動 (2016)
  • Author(s): 堀 正敏
  • Organizer: 第12回日本食品免疫学会学術大会
  • Place of Presentation: 東京大学伊藤国際ホール（東京都・文京区）
  • Year and Date: 2016-11-09
  • Invited
• [Presentation] ミオシンホスファターゼ阻害因子CPI-17の機能欠損による大腸輸送能遅延 (2016)
  • Author(s): 槙 郁風、藤井 渉、角田 茂、梶 典幸、楊 群輝、尾崎 博、堀 正敏
  • Organizer: 第18回日本神経消化器病学会
  • Place of Presentation: 北海道大学医学部（北海道・札幌市）
  • Year and Date: 2016-09-09
• [Presentation] The function of intestinal pacemaker cells is impaired by nitric oxide derived from resident macrophages and smooth muscle cells during Th1 inflammation. (2016)
  • Author(s): Kaji N, Horiguchi K, Iino S, Nakayama S, Ozaki H and Hori M.
  • Organizer: The 24th International Symposium on Molecular Cell Biology of Macrophages (MMCB2016)
  • Place of Presentation: Sola City Conference Center (Tokyo・Chiyoda-ku)
  • Year and Date: 2016-06-04
  • Int'l Joint Research
• [Remarks] 東京大学大学院農学生命科学研究科 獣医薬理学教室
  • URL: http://www.vm.a.u-tokyo.ac.jp/yakuri/
• [Remarks] 東京大学 大学院農学生命科学研究科 獣医薬理学教室
  • URL: http://www.vm.a.u-tokyo.ac.jp/yakuri/