Epigenetic regulation of macrophage function in inflammatory bowel disease

• Project/Area Number: 25460960
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kitasato University
• Principal Investigator: Kobayashi Taku 北里大学, 北里研究所病院, 特任准教授 (10424144)
• Co-Investigator(Kenkyū-buntansha): NAKANO Masaru 北里大学, 北里研究所病院, 部長(医師) (50265807)
• Co-Investigator(Renkei-kenkyūsha): ASAI Tomohiro 静岡県立大学, 薬学部, 准教授 (00381731)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 炎症性腸疾患 / エピゲノム / マクロファージ / クロマチン構造 / HDAC阻害剤 / 腸管マクロファージ / FAIRE

Outline of Final Research Achievements

We hypothesized that profiling accessible chromatin where transcription factors bind in intestinal cells from affected and non-affected individuals would identify genetically driven regulatory elements that are relevant to IBD pathology. 74 IBD associated SNPs were found in regions of open chromatin. There was statistically significant enrichment of IBD associated SNPs in regions of open chromatin in CD tissue compared to a set of random selected DNA variants with similar architecture.
Drug development based on the epigenetic modification was also attempted. Histone deacethylase inhibitors were tested for cytokine inhibition in bone-marrow derived macrophages. Belinostat showed a tendency to ameliorate acute and chronic DSS-induced colitis models.

Research Products

• [Int'l Joint Research] University of North Carolina(米国)
• [Journal Article] Involvement of herbal medicine as a cause of mesenteric phlebosclerosis: results from a large-scale nationwide survey (2016)
  • Author(s): Shimizu S, Kobayashi T, Tomioka H, Ohtsu K, Matsui T, Hibi T. .
  • Journal Title: J Gastroenterol Volume: in press
  • Peer Reviewed
• [Journal Article] First trough level of infliximab at week 2 predicts future outcomes of induction therapy in ulcerative colitis - results from a multicenter prospective randomized controlled trial and its post-hoc analysis. (2016)
  • Author(s): Kobayashi T, Suzuki Y, Motoya S, Hirai F, Ogata H, Ito H, Sato N, Osaki K, Watanabe M, Hibi T
  • Journal Title: J Gastroenterol Volume: 51(3) Issue: 3 Pages: 241-51
  • DOI: 10.1007/s00535-015-1102-z
  • Peer Reviewed / Open Access
• [Journal Article] Modified bowel preparation regimen for use in second-generation colon capsule endoscopy in patients with ulcerative colitis (2014)
  • Author(s): Usui S, Hosoe N, Matsuoka K, Kobayashi T, Nakano M, Naganuma M, Ishibashi Y, Kimura K, Yoneno K, Kashiwagi K, Hisamatsu T, Inoue N, Serizawa H, Hibi T, Ogata H, Kanai T.
  • Journal Title: Digestive Endoscopy Volume: 26(5) Issue: 5 Pages: 665-72
  • DOI: 10.1111/den.12269
  • Peer Reviewed
• [Journal Article] Ulcerative colitis: Which makes patients happier, surgery or anti-TNF? (2014)
  • Author(s): Kobayashi T and Hibi T
  • Journal Title: Nat Rev Gastroenterol Hepatol Volume: 11 Issue: 5 Pages: 272-273
  • DOI: 10.1038/nrgastro.2014.28
• [Journal Article] NFIL3-Deficient Mice Develop Microbiota-Dependent, IL-12/23-Driven Spontaneous Colitis. (2014)
  • Author(s): Kobayashi, T., Steinbach, E.C., Russo, S.M., Matsuoka, K., Nochi, T., Maharshak, N., Borst, L.B., Hostager, B., Garcia-Martinez, J.V., Rothman, P.B., Kashiwada, M., Sheikh, S.Z., Murray, P.J. and Plevy, S.E.
  • Journal Title: Journal of Immunology Volume: 192 Issue: 4 Pages: 1918-1927
  • DOI: 10.4049/jimmunol.1301819
  • Peer Reviewed
• [Journal Article] 潰瘍性大腸炎とクローン病は何がどう違うのか（１）免疫学的違いは？ (2014)
  • Author(s): 小林拓
  • Journal Title: Medicina Volume: 51 Pages: 1004-1007
• [Journal Article] Innate PI3K p110δ regu lates Th1/Th17 development and microbiota-dependent colitis. (2014)
  • Author(s): Steinbach EC, Kobayashi T, Russo SM, Sheikh SZ, Gipson G, Kennedy S, Uno JK, Mishima Y, Borst LB, Liu B, Herfarth H, Ting J, Sartor RB, Plevy SE
  • Journal Title: J Immunol Volume: 192 Issue: 8 Pages: 3958-3968
  • DOI: 10.4049/jimmunol.1301533
  • Peer Reviewed
• [Presentation] 臨床免疫学的アプローチから見た炎症性腸疾患感受性遺伝子 (2015)
  • Author(s): 小林拓
  • Organizer: 第43回日本臨床免疫学会総会ワークショップ３
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-10-21
  • Invited
• [Presentation] 24.First trough level of infliximab at week 2 predicts future outcomes of induction therapy in ulcerative colitis-A post-hoc analysis of a multicenter prospective randomized controlled trial (2015)
  • Author(s): Kobayashi T
  • Organizer: ACG Annual scientific Meeting
  • Place of Presentation: Honolulu (USA)
  • Year and Date: 2015-10-18
  • Int'l Joint Research
• [Presentation] Usefulness of fecal S100A12 in defining mucosal healing in ulcerative colitis (2015)
  • Author(s): Kobayashi T
  • Organizer: 3rd Asian Organization of Crohn's and Colitis
  • Place of Presentation: Beijing (China)
  • Year and Date: 2015-06-19
  • Int'l Joint Research
• [Presentation] IBD粘膜固有層単核細胞分離技術を応用したエピゲノム、代謝研究とその人種差検討 (2015)
  • Author(s): 小林拓
  • Organizer: 「難治性炎症性腸管障害に関する調査研究」平成27年度第１回総会
  • Place of Presentation: 味の素㈱本社ビル（東京都中央区）
  • Year and Date: 2015-01-22 – 2015-01-23
• [Presentation] 炎症性腸疾患感受性遺伝子NFIL3の機能とその欠損マウスにおける腸炎の発症機序解明 (2014)
  • Author(s): 小林拓
  • Organizer: 第42回日本臨床免疫学会総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2014-09-25
• [Presentation] IBD粘膜固有層単核細胞分離技術を応用したエピゲノム、代謝研究とその人種差検討 (2014)
  • Author(s): 小林拓
  • Organizer: 「難治性炎症性腸管障害に関する調査研究」平成26年度第2回総会
  • Place of Presentation: 味の素㈱本社ビル（東京都中央区）
  • Year and Date: 2014-07-23 – 2014-07-24
• [Presentation] 炎症性腸疾患感受性遺伝子NFIL3欠損マウスは自然免疫異常を介し腸炎を自然発症する (2014)
  • Author(s): 小林拓
  • Organizer: 第51回消化器免疫学会総会
  • Place of Presentation: 京都大学医学部 芝蘭会館（京都市）
  • Year and Date: 2014-07-11
• [Presentation] Genetically Driven Chromatin Organization Identifies Regulatory SNPs Associated with Crohn's Disease (2014)
  • Author(s): Matthew Weiser, Chelsea Raulerson, Adam Robinson, Gregory Gipson, Tomohisa Sujino, Osamu Takeuchi, Taku Kobayashi, Hans H. Herfarth, Ryan B. Sartor, Dermot P. McGovern, Jason D. Lieb, Terrence S. Furey, Shehzad Z. Sheikh
  • Organizer: DDW2014
  • Place of Presentation: Chicago, USA