Roles of angiocrine factors in the pathophysiological regulation systems of inflammatory bowel diseases

• Project/Area Number: 18K08657
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Juntendo University
• Principal Investigator: OSADA TARO 順天堂大学, 医学部, 教授 (00338336)
• Co-Investigator(Kenkyū-buntansha): 服部 浩一 順天堂大学, 大学院医学研究科, 特任先任准教授 (10360116)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 小腸大腸肛門外科学 / 下部消化管学 / 生体分子 / 細胞・組織 / 炎症性腸疾患 / 細胞・組織、生体分子

Outline of Final Research Achievements

In previous studies, the applicants have found that the production and secretion of angiocrine molecules from the vascular endothelium, including blood coagulation / fibrinolytic factors and matrix metalloproteases, are involved in the pathophysiology of inflammatory bowel disease (IBD). Recent studies reported that thromboembolism is known as an extraintestinal complication of IBD, suggesting the presence of vascular endothelial injury. In this study, we will advance the detailed elucidation of vascular endothelial disorders and dysfunctions in IBD, elucidate the dynamics of blood or stool angiocrine molecules in IBD, and the pathological and pathological control mechanism of IBD, and vascular endothelium and other cell types. The details of soluble factor interaction with cells were clarified. Finally, we succeeded in presenting new molecular therapies for IBD targeting angiocrine molecules, laying the foundation for the development of adjuvant therapies, and candidate factors.

Academic Significance and Societal Importance of the Research Achievements

IBDに対する治療は、副腎皮質ステロイドを始めとする経口抗炎症薬に加え。近年、TNF-αに代表される生物製剤、血球成分除去療法が臨床に普及し、その治療予後は有意に改善しつつあるが、未だ厳然と内科的治療の不応例が存在することが判明しており、IBDの長期的な予後、QOLの改善、またその病勢制御に、本研究成果は必須な知見を提示した。また静脈血栓塞栓症は、IBDの予後にも影響する、深刻かつ多発する重要な合併症として知られているが、本研究成果は、この合併症の要因こそが、IBD病勢の制御因子であること、そしてこれを標的とした分子療法こそが、IBDにとっても重要な治療法となる可能性を示唆したと言える。

Research Products

• [Journal Article] Efficacy of cytapheresis for induction therapy and extra‐intestinal skin manifestations of ulcerative colitis (2022)
  • Author(s): Shibuya Tomoyoshi、Nomura Osamu、Nomura Kei、Haraikawa Mayuko、Haga Keiichi、Ishikawa Dai、Osada Taro、Yamaji Ken、Ikeda Shigaku、Nagahara Akihito
  • Journal Title: Therapeutic Apheresis and Dialysis Volume: in press Issue: 3 Pages: 522-528
  • DOI: 10.1111/1744-9987.13823
  • Peer Reviewed
• [Journal Article] Nicotine Oral Administration Attenuates DSS-Induced Colitis Through Upregulation of Indole in the Distal Colon and Rectum in Mice (2021)
  • Author(s): Nakajima Akihito、Shibuya Tomoyoshi、Sasaki Takashi、Lu Yu Jie、Ishikawa Dai、Haga Keiichi、Takahashi Masahito、Kaga Naoko、Osada Taro、Sato Nobuhiro、Nagahara Akihito
  • Journal Title: Frontiers in Medicine Volume: 8
  • DOI: 10.3389/fmed.2021.789037
  • Peer Reviewed / Open Access
• [Journal Article] Bacteroidetes Species Are Correlated with Disease Activity in Ulcerative Colitis (2021)
  • Author(s): Nomura Kei、Ishikawa Dai、Okahara Koki、Ito Shoko、Haga Keiichi、Takahashi Masahito、Arakawa Atsushi、Shibuya Tomoyoshi、Osada Taro、Kuwahara-Arai Kyoko、Kirikae Teruo、Nagahara Akihito
  • Journal Title: Journal of Clinical Medicine Volume: 10 Issue: 8 Pages: 1749-1749
  • DOI: 10.3390/jcm10081749
  • Peer Reviewed
• [Journal Article] The multifaceted roles of EGFL7 in cancer and drug resistance. (2021)
  • Author(s): Heissig B*, Salama Y, Takahashi S, Okumura K, Hattori K
  • Journal Title: Cancers Volume: 13(5) Issue: 5 Pages: 1014-1014
  • DOI: 10.3390/cancers13051014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The multifacted role of plasminogen in Cancer. (2021)
  • Author(s): Heissig B*, Salama Y, Osada T, Okumura K, Hattori K.
  • Journal Title: Intern. J of Molecular Sciences Volume: 22(5) Issue: 5 Pages: 2304-2304
  • DOI: 10.3390/ijms22052304
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Matching between Donors and Ulcerative Colitis Patients Is Important for Long-Term Maintenance after Fecal Microbiota Transplantation (2020)
  • Author(s): Okahara Koki、Ishikawa Dai、Nomura Kei、Ito Shoko、Haga Keiichi、Takahashi Masahito、Shibuya Tomoyoshi、Osada Taro、Nagahara Akihito
  • Journal Title: Journal of Clinical Medicine Volume: 9 Issue: 6 Pages: 1650-1650
  • DOI: 10.3390/jcm9061650
  • Peer Reviewed / Open Access
• [Journal Article] Effectiveness and Nephrotoxicity of Long-Term Tacrolimus Administration in Patients with Ulcerative Colitis (2020)
  • Author(s): Haga Keiichi、Shibuya Tomoyoshi、Nomura Kei、Okahara Koki、Nomura Osamu、Ishikawa Dai、Sakamoto Naoto、Osada Taro、Nagahara Akihito
  • Journal Title: Journal of Clinical Medicine Volume: 9 Issue: 6 Pages: 1771-1771
  • DOI: 10.3390/jcm9061771
  • Peer Reviewed
• [Journal Article] The multifaceted role of plasminogen in inflammation (2020)
  • Author(s): Heissig Beate、Salama Yousef、Takahashi Satoshi、Osada Taro、Hattori Koichi
  • Journal Title: Cellular Signalling Volume: 75 Pages: 109761-109761
  • DOI: 10.1016/j.cellsig.2020.109761
  • Peer Reviewed / Open Access
• [Journal Article] The EGFL7-ITGB3-KLF2 axis enhances survival of multiple myeloma in preclinical models. (2020)
  • Author(s): Salama Y, Andries H, Yokoyama K, Takahashi S Hattori K and Heissig B,.
  • Journal Title: Blood Adv Volume: in press Issue: 6 Pages: 1021-1037
  • DOI: 10.1182/bloodadvances.2019001002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 線溶系と炎症性疾患 (2020)
  • Author(s): 服部浩一、 高橋聡、 長田太郎、Heissig Beate
  • Journal Title: 日本血栓止血学会雑誌 Volume: 31(4) Pages: 388-393
  • NAID: 130007887022
  • Peer Reviewed
• [Journal Article] 腸管外合併症に対するGMAの有効性 (2020)
  • Author(s): 長田太郎、野村 収、荻原伸悟、服部浩一
  • Journal Title: 日本アフェレーシス学会雑誌 Volume: 39(2) Pages: 100-107
  • Peer Reviewed
• [Journal Article] Safety and effectiveness of granulocyte and monocyte adsorptive apheresis in patients with inflammatory bowel disease in special situations: a multicentre cohort study. (2019)
  • Author(s): Motoya S, Tanaka H, Shibuya T, Osada T, Yamamoto T, Hongo H, Mizuno C, Saito D, Aoyama N, Kobayashi T, Ito H, Tanida S, Nojima M, Kokuma S, Hosoi E.
  • Journal Title: BMC Gastroenterol. Volume: 19 Issue: 1 Pages: 196-196
  • DOI: 10.1186/s12876-019-1110-1
  • Peer Reviewed / Open Access
• [Journal Article] The fibrinolytic factor tPA drives LRP1-mediated melanoma growth and metastasis (2019)
  • Author(s): Salama Y, Lin SY, Dhahri D, Hattori K, Heissig B
  • Journal Title: FASEB J Volume: 33 Issue: 3 Pages: 3465-3480
  • DOI: 10.1096/fj.201801339rrr
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] クローン病におけるブデソニド腸溶性徐放製剤使用例からみた有用性の検討 (2022)
  • Author(s): 矢野慎太郎, 石野博崇, 松下瑞季, 山内友愛, 磯野峻輔, 大川博基, 中津洋一, 西慎二郎, 深見久美子, 野元勇佑, 荻原伸悟, 岩本志穂, 降籏誠, 北村庸雄, 長田太郎
  • Organizer: 第18回日本消化管学会学術集会
• [Presentation] 直近4年におけるクローン病の初回治療から寛解までの臨床経過に関する検討 (2021)
  • Author(s): 矢野慎太郎, 神保泰久, 牛尾真子, 磯野峻輔, 大川博基, 中津洋一, 西慎二郎, 深見久美子, 野元勇佑, 荻原伸悟, 降籏誠, 岩本志穗, 北村庸雄, 長田太郎
  • Organizer: 第29回日本消化器関連学会週間
• [Presentation] 潰瘍性大腸炎患者の発症年齢による初回治療から寛解までの臨床経過に関する検討 (2021)
  • Author(s): 矢野慎太郎, 牛尾真子, 磯野峻輔, 大川博基, 多田昌弘, 中津洋一, 西慎二郎, 深見久美子, 野元勇佑, 荻原伸悟, 降籏誠, 岩本志穗, 北村庸雄, 長田太郎
  • Organizer: 第107回 日本消化器病学会総会
• [Presentation] クローン病に対して ブデソニド腸溶性徐放性剤を 使用した寛解導入効果の検討 (2021)
  • Author(s): 矢野慎太郎、石野博崇、松下瑞季、山内友愛、磯野峻輔、大川博基、中津洋一、西慎二郎、深見久美子、野元勇佑、荻原伸悟、降旗誠、岩本志穗、北村庸雄、長田太郎
  • Organizer: 第12回日本炎症性腸疾患学会学術集会
• [Presentation] Fibrinolytic factors - novel molecular targets for cytokine storm-associated diseases (2021)
  • Author(s): Hattori K, Takahashi S and Heissig B.
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] アンジオクラインシステムによるサイトカインストーム制御機構の解明 (2021)
  • Author(s): 9. 服部浩一, 高橋聡, 長田太郎, Heissig Beate
  • Organizer: 第20回日本再生医療学会総会
• [Presentation] 潰瘍性大腸炎（UC）における顆粒球単球吸着療法（GMA）の治療前後におけるMMP-9の変動について. (2020)
  • Author(s): 野村収 長田太郎 服部浩一 澁谷智義 草生真規雄 山路 健 永原章仁
  • Organizer: 第41回アフェレーシス学会
• [Presentation] 臓器特異的血管内皮によるアンジオクラインシステム制御機構の解明 (2020)
  • Author(s): 服部浩一, 高橋聡 Heissig Beate.
  • Organizer: 第19回日本再生医療学会総会
• [Presentation] Safety and effectiveness of retreatment with granulocyte and monocyte adsorptive apheresis in patients with inflammatory bowel diseases: a multicenter cohort study. (2019)
  • Author(s): Shibuya T. Osada T. Yamamoto T. Shimoyama T. Aoyama N. Mizuno C. Tanaka H. Hongo H. Masuda T. Hosoi E.
  • Organizer: UEGW 2019
  • Int'l Joint Research
• [Presentation] Roles of the fibrinolytic system in the pathogenesis of inflammatory diseases. (2019)
  • Author(s): Hattori K, Takahashi S and Heissig B
  • Organizer: 第41回日本血栓止血学会学術集会
  • Invited
• [Presentation] Influence of Adsorptive Granulocyte and Monocyte Apheresis on Fibrinolytic System and Matrix Metalloproteinase-9 in Patients with Ulcerative Colitis. (2018)
  • Author(s): Osamu Nomura, Taro Osada, Tomoyoshi Shibuya, Dai Ishikawa, Tomohiro Kodani, Keiichi Haga, Masato Kamei, Naoto Sakamoto, Sumio Watanabe.
  • Organizer: 6th Annual Meeting of the Asian Organization for Crohn's and Colitis
  • Int'l Joint Research
• [Presentation] HSC expansion and mobilization from bone marrow niche. (2018)
  • Author(s): Hattori K
  • Organizer: OINT WORK SHOP NORWAY AND JAPAN IN REGENERATIVE MEDICINE
• [Presentation] Angiocrine system regulates macrophage -dependent aberrant tissue repair and remodeling (2018)
  • Author(s): Hattori K, Takahashi, Heissig B
  • Organizer: 第80回日本血液学会学術集会
• [Book] 現場で知りたいIBD診療のすべて 比べてわかる!潰瘍性大腸炎とクローン病 (2021)
  • Author(s): 矢野慎太郎、長田太郎
  • Total Pages: 3
  • Publisher: 日本医事新報社
• [Book] 炎症と免疫 (2020)
  • Author(s): 服部浩一、 高橋聡、 長田太郎、Heissig Beate
  • Total Pages: 6
  • Publisher: 先端医学社