Development of mucosa-regenerating therapy through comprehensive analysis of intestine-specific Notch target genes

2008 Fiscal Year Final Research Report

• Project/Area Number: 19890064
• Research Category: Grant-in-Aid for Young Scientists (Start-up)
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: OKAMOTO Ryuichi Tokyo Medical and Dental University, 大学院・医歯学総合研究科, 寄附講座准教授 (50451935)
• Project Period (FY): 2007 – 2008
• Keywords: 炎症性腸疾患 / 粘膜再生 / Notchシグナル

Research Abstract

本研究では炎症性腸疾患、特に潰瘍性大腸炎患者の炎症部に於ける上皮分化制御の分子機構と粘膜再生メカニズムに焦点をあて、粘膜再生促進につながる分子標的の探索を行った。我々が独自に樹立したヒト腸管上皮培養細胞株及び患者臨床検体を用いた分子生物学的探索により、炎症性腸疾患患者の粘膜上皮に於ける再生促進に寄与する主たる分子シグナルとしてNotchシグナルを同定した。同シグナルは炎症性腸疾患に特徴的な上皮分化様式を決定するシグナル経路であるのみならず、細胞増殖を介した粘膜再生に積極的に関与し、同シグナル活性化の欠如が即ち粘膜再生不全につながることを明確に示した。さらに、ヒト腸管上皮細胞におけるNotch活性化により制御される遺伝子群の網羅的探索により、粘膜再生応答における腸管上皮細胞トランスクリプトームを明らかとし、粘膜再生治療に於ける新規標的分子探索の基盤を構築した。これらの成果は炎症性腸疾患における難治化の主たる要因である粘膜再生不全の機序を分子レベルで解明した画期的知見であるのみならず、特定のシグナル活性化を誘導することにより粘膜再生を促進する新規治療法の開発に重要な分子基盤を確立したものである。

Research Products

• [Journal Article] Requirement of Notch activation during regeneration of the intestinal epithelia (2009)
  • Author(s): Okamoto R, Tsuchiya K, et.al.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 296 Pages: G23-35
  • Peer Reviewed
• [Journal Article] Musashi-1 suppresses expression of Paneth cell specific genes in human intestinal epithelial cells (2009)
  • Author(s): Murayama M, Okamoto R, Tsuchiya K, Akiyama J, Nakamura T, Sakamoto N, Kanai T, Watanabe M
  • Journal Title: J Gastroenterol 44(3) Pages: 173-182
  • Peer Reviewed
• [Journal Article] Colitogenic CD4(+)effector-memory T cells activelyrecirculate in chronic colitic mice (2008)
  • Author(s): Tomita T, Kanai T, Nemoto Y, FujiiT, Nozaki K, Okamoto R, Tsuchiya K, Nakamura T, Totsuka T, Watanabe M
  • Journal Title: Inflamm Bowel Dis (in press)
  • Peer Reviewed
• [Journal Article] Flagellin stimulation suppresses IL-7 secretion of intestinal epithelial cells (2008)
  • Author(s): Yoshioka A, Okamoto R, Oshima S, Akiyama J, Tsuchiya K, Nakamura T, Kanai T, Watanabe M
  • Journal Title: Cytokine 44(1) Pages: 57-64
  • Peer Reviewed
• [Journal Article] Negative feedback regulation of colitogenic CD4(+)T cells by increased granulopoiesis (2008)
  • Author(s): Nemoto Y, Kanai T, Tohda S, TotsukaT, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Fukuda T, Miura O, Yagita H, Watanabe M
  • Journal Title: Inflamm Bowel Dis 14(11) Pages: 1491-503
  • Peer Reviewed
• [Journal Article] Inducible expression of microRNA-194 is regulated by HNF-1alpha during intestinal epithelial cell differentiation (2008)
  • Author(s): Hino K, Tsuchiya K, Fukao T, Kiga K, Okamoto R, Kanai T, Watanabe M
  • Journal Title: RNA 14(7) Pages: 1433-42
  • Peer Reviewed
• [Journal Article] Immunosenescent colitogenic CD4(+)T cells convert to regulatory cells and suppress colitis (2008)
  • Author(s): Totsuka T, Kanai T, Nemoto Y, TomitaT, Tsuchiya K, Sakamoto N, Okamoto R, Watanabe M
  • Journal Title: Eur J Immunol 38(5) Pages: 1275-86
  • Peer Reviewed
• [Journal Article] MyD88-dependent pathway in T cellsdirectly modulates the expansionof colitogenic CD4+ T cells inchronic colitis (2008)
  • Author(s): Tomita T, Kanai T, Fujii T, NemotoY, Okamoto R, Tsuchiya K, TotsukaT, Sakamoto N, Akira S, Watanabe M
  • Journal Title: J Immunol 180(8) Pages: 5291-9
  • Peer Reviewed
• [Journal Article] Proteasomal degradation of Atoh1 by aberrant Wnt signaling maintains the undifferentiated state of colon cancer (2008)
  • Author(s): Aragaki M, Tsuchiya K, Okamoto R, Yoshioka S, Nakamura T, Sakamoto N, Kanai T, Watanabe M
  • Journal Title: Biochem Biophys Res Commun 368(4) Pages: 923-9
  • Peer Reviewed
• [Journal Article] Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis (2008)
  • Author(s): Tomita T, Kanai T, Nemoto Y, TotsukaT, Okamoto R, Tsuchiya K, SakamotoN, Watanabe M
  • Journal Title: J Immunol 180(1) Pages: 383-90
  • Peer Reviewed
• [Journal Article] Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-mediated colitis (2008)
  • Author(s): Ito Y, Kanai T, Totsuka T, Okamoto R, Tsuchiya K, Nemoto Y, Yoshioka A, Tomita T, Nagaishi T, Sakamoto N, Sakanishi T, Okumura K, Yagita H, Watanabe M
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 294(1) Pages: G199-207
  • Peer Reviewed
• [Journal Article] Intestinal lamina propria retaining CD4+CD25+regulatory T cells is a suppressive site of intestinal inflammation (2007)
  • Author(s): Makita S, Kanai T, Nemoto Y, Totsuka T, Okamoto R, Tsuchiya K, Yamamoto M, Kiyono H, Watanabe M
  • Journal Title: J Immunol 178(8) Pages: 4937-46
  • Peer Reviewed
• [Journal Article] IL-7 Is essential for the development and the persistence of chronic colitis (2007)
  • Author(s): Totsuka T, Kanai T, Nemoto Y, Makita S, Okamoto R, Tsuchiya K, Watanabe M
  • Journal Title: J Immunol 178(8) Pages: 4737-48
  • Peer Reviewed
• [Journal Article] Reciprocal targeting of Hath1 and beta-cateninby Wnt-glycogen synthase kinase 3 beta in human colon cancer (2007)
  • Author(s): Tsuchiya K, Nakamura T, Okamoto R, Kanai T, Watanabe M
  • Journal Title: Gastroenterology 132(1) Pages: 208-220
  • Peer Reviewed
• [Journal Article] Bone Marrow Retaining Colitogenic CD4(+) T Cells May Be a Pathogenic Reservoir for Chronic Colitis (2007)
  • Author(s): Nemoto Y, Kanai T, Makita S, OkamotoR, Totsuka T, Takeda K, Watanabe M
  • Journal Title: Gastroenterology 132(1) Pages: 176-189
  • Peer Reviewed
• [Presentation] Tsuchiya : Dysregulated differentiation of intestinal epithelia in UC (2008)
  • Author(s): Okamoto R
  • Organizer: 3rd Japan-Korea IBD Symposium
  • Place of Presentation: ソウル
  • Year and Date: 2008-09-20
• [Presentation] Neutralization of tumor necrosis factor suppresses the development of colitis-associated tumor in mice (2008)
  • Author(s): Onizawa M, Nagaishi T, Nemoto Y, Oshima S, Okamoto R, et.al.
  • Organizer: DDW2008
  • Place of Presentation: San Diego
  • Year and Date: 2008-05-21
• [Presentation] Notch signaling suppresses the transcriptional activity of Hathl Gene, resulting in the undifferentiated form of human intestinal epithelial cells (2008)
  • Author(s): Tsuchiya K, Inoue K, Aragaki M, Okamoto R et.al.
  • Organizer: DDW 2008
  • Place of Presentation: San Diego
  • Year and Date: 2008-05-20
• [Presentation] Role of Notch signaling in inflammatory bowel diseases (2007)
  • Author(s): Okamoto R
  • Organizer: アジア太平洋消化器病学会
  • Place of Presentation: 神戸
  • Year and Date: 2007-10-16
• [Presentation] Activated Notch Signalling Suppresses Generation of Goblet Cellsin the Human Intestinal Mucosa (2007)
  • Author(s): Okamoto R
  • Organizer: DDW 2007
  • Place of Presentation: ワシントン
  • Year and Date: 2007-05-20