Examination of regulatory network profiles for gene expression of intestinal epithelial barrier dysfunction in aging

• Project/Area Number: 16K08581
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Mie University
• Principal Investigator: PARK Eun Jeong 三重大学, 医学系研究科, 准教授 (20644587)
• Co-Investigator(Kenkyū-buntansha): 島岡 要 三重大学, 医学系研究科, 教授 (40281133)
• Research Collaborator: KIYONO Hiroshi ; MIZUGUCHI Kenji
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 老化 / マイクロRNA / 腸管上皮細胞 / エキソソーム / T細胞 / ホーミング / インテグリン / 粘膜組織 / 敗血症モデル / 腸炎 / リンパ球ホーミング / 免疫学

Outline of Final Research Achievements

To elucidate the molecular mechanism of regulating comprehensive gene expressions in intestinal epithelial cells in aging, we analyzed miRNA profiling of epithelial cells in small and large intestines of aged mice. As a result, multiple miRNAs were found to be altered by aging.
To understand the role of T-cell exosomes in tissue specific homing of lymphocytes, we isolated the exosomes from the culture of gut-tropic T cells and analyzed in-vivo homing of lymphocytes. We have found that the exosomes　possess　an　ability　in　negatively　regulating subsequent lymphocyte homing to the gut. This negative effect was considered to be due to expression reduction of the ligand molecules important for lymphocyte homing, possibly by exosomal delivery of miRNAs to the gut endothelial cells.

Academic Significance and Societal Importance of the Research Achievements

生体防御システムである免疫系の老化は、老化による免疫系の機能減退の分子メカニズムの解明は非常に重要な研究課題である。老化に伴う腸管上皮細胞の遺伝子発現調節の分子機序を明らかにすることは重要であり、本研究有意な発現変化を示す多数のマイクロRNAは、今後粘膜免疫関連アンティエイジング研究に結び付ける重要な基礎資料になると考えられる。
腸管移行性T細胞のエキソソームがリンパ球に先回り腸管内皮細胞に、マイクロRNAを伝達し、腸管組織特異的にリンパ球ホーミングを負に制御するという仮説の検証は、新たな炎症性腸疾患治療に向けての基礎研究で創造性が高いと考えられる。

Research Products

• [Journal Article] Talin-2 regulates integrin functions in exosomes (2019)
  • Author(s): Soe Zay Yar、Prajuabjinda Onmanee、Myint Phyoe Kyawe、Gaowa Arong、Kawamoto Eiji、Park Eun Jeong、Shimaoka Motomu
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 512 Issue: 3 Pages: 429-434
  • DOI: 10.1016/j.bbrc.2019.03.027
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-adhesive effects of human soluble thrombomodulin and its domains (2019)
  • Author(s): Kawamoto Eiji、Nago Nodoka、Okamoto Takayuki、Gaowa Arong、Masui-Ito Asami、Sakakura Yosuke、Akama Yuichi、Soe Zay Yar、Prajuabjinda Onmanee、Darkwah Samuel、Appiah Michael G.、Myint Phyoe Kyawe、Obeng Gideon、Park Eun Jeong、Imai Hiroshi、Shimaoka Motomu
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 511 Issue: 2 Pages: 312-317
  • DOI: 10.1016/j.bbrc.2019.02.041
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Connexins and Integrins in Exosomes (2019)
  • Author(s): Shimaoka M, Kawamoto E, Gaowa A, Okamoto T, Park EJ
  • Journal Title: Cancers (Basel) Volume: － Issue: 1 Pages: 106-106
  • DOI: 10.3390/cancers11010106
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exosomal regulation of lymphocyte homing to the gut (2018)
  • Author(s): Park Eun Jeong、Prajuabjinda Onmanee、Soe Zay Yar、Darkwah Samuel、Appiah Michael G.、Kawamoto Eiji、Momose Fumiyasu、Shiku Hiroshi、Shimaoka Motomu
  • Journal Title: Blood Advances Volume: 3 Issue: 1 Pages: 1-11
  • DOI: 10.1182/bloodadvances.2018024877
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrin and PD-1 Ligand Expression on Circulating Extracellular Vesicles in Systemic Inflammatory Response Syndrome and Sepsis (2018)
  • Author(s): Kawamoto Eiji、Masui-Ito Asami、Eguchi Akiko、Soe Zay Yar、Prajuabjinda Onmanee、Darkwah Samuel、Park Eun Jeong、Imai Hiroshi、Shimaoka Motomu
  • Journal Title: SHOCK Volume: - Issue: 1 Pages: 1-1
  • DOI: 10.1097/shk.0000000000001228
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Eosinophil depletion suppresses radiation-induced small intestinal fibrosis. (2018)
  • Author(s): Takemura N, Kurashima Y, Mori Y, Okada K, Ogino T, Osawa H, Matsuno H, Aayam L, Kaneto S, Park EJ, Sato S, Matsunaga K, Tamura Y, Ouchi Y, Kumagai Y, Kobayashi D, Suzuki Y, Yoshioka Y, Nishimura J, Mori M, Ishii KJ, Rothenberg ME, Kiyono H, Akira S, Uematsu S.
  • Journal Title: Sci Transl Med. Volume: -- Issue: 429 Pages: 264-273
  • DOI: 10.1126/scitranslmed.aan0333
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of immune and microbial environment is independently regulated in the mammary gland (2018)
  • Author(s): Niimi K, Usami K, Fujita Y, Abe M, Furukawa M, Suyama Y, Sakai Y, Kamioka M, Shibata N, Park EJ, Sato S, Kiyono H, Yoneyama H, Kitazawa H, Watanabe K, Nochi T, Aso H
  • Journal Title: Mucosal Immunology Volume: 印刷中 Issue: 3 Pages: 643-653
  • DOI: 10.1038/mi.2017.90
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] インテグリン活性化と炎症制御 (2018)
  • Author(s): 島岡 要、長太 のどか、川本 英嗣、朴 恩正
  • Journal Title: Shock (発行元：日本Shock学会) Volume: 32 Pages: 48-51
• [Journal Article] Reduced substrate stiffness promotes M2-like macrophage activation and enhances peroxisome proliferator-activated receptor-gamma expression (2018)
  • Author(s): Okamoto T, Takagi Y, Kawamoto E, Park EJ, Usuda H, Wada K, Shimaoka M
  • Journal Title: Experimental Cell Research Volume: 367 Issue: 2 Pages: 264-273
  • DOI: 10.1016/j.yexcr.2018.04.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gap junction-mediated regulation of endothelial cellular stiffness (2018)
  • Author(s): Okamoto T, Kawamoto E, Takagi Y, Akita N, Hayashi T, Park EJ, Suzuki K, Shimaoka M
  • Journal Title: Scientific Reports Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA-mediated dynamic control of mucosal immunity in intestinal ecosystem. (2017)
  • Author(s): Park, EJ., Shimaoka, M. and Kiyono, H.
  • Journal Title: International Immunology Volume: - Issue: 4 Pages: 157-163
  • DOI: 10.1093/intimm/dxx019
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Critical role of TSLP-responsive mucosal DCs for the induction of nasal antigen-specific IgA response. Mucosal Immunol. (2017)
  • Author(s): Joo,S., Fukuyama, Y., Park,E-J., Yuki, Y., Kurashima, Y., Ziegler, S.F. and Kiyono,H.
  • Journal Title: Mucosal Immunology Volume: - Issue: 4 Pages: 901-911
  • DOI: 10.1038/mi.2016.103
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 抗老化に向けた腸管上皮細胞と細胞外小胞のマイクロRNA遺伝子情報データベース構築 (2016)
  • Author(s): 朴 恩正
  • Journal Title: アレルギーの臨床 Volume: 36 Pages: 1278-1280
• [Journal Article] MicroRNA-orchestrated pathophysiologic control in gut homeostasis and inflammation (2016)
  • Author(s): Lee J, Park EJ, Kiyono H
  • Journal Title: BMB Reports Volume: 49 Pages: 263-269
  • Peer Reviewed
• [Journal Article] LFA-1 and Mac-1 integrins bind to the serine/threonine-rich domain of thrombomodulin. (2016)
  • Author(s): Okamoto T, Kawamoto E, Takagi Y, Honda G, Suzuki K, Ima H, Shimaoka M
  • Journal Title: Biochem Biophys Res Commun Volume: 473 Issue: 4 Pages: 1005-1012
  • DOI: 10.1016/j.bbrc.2016.04.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Intraluminally secreted extracellular vesicles from the intestinal epithelial cells in sepsis support mucosal healing (2018)
  • Author(s): Park EJ, Appiah MG, Darkwah S, Soe ZY, Kawamoto E, Shimaoka M
  • Organizer: 第47回 日本免疫学会
• [Presentation] Integrin and PD-1 ligand expression on circulating extracellular vesicles in systemic inflammatory response syndrome and sepsis (2018)
  • Author(s): Kawamoto E, Masui-Ito A, Eguchi A, Soe ZY, Prajuabjinda O, Park EJ, Imai H, Shimaoka M
  • Organizer: 41st Annual Conference on Shock
  • Int'l Joint Research
• [Presentation] LPS肝炎に続く敗血症性炎症病変における腹部内進展のMRIイメージング (2017)
  • Author(s): 長太 のどか、米田 操、朴 恩正、島岡 要
  • Organizer: 第32回 日本ショック学会
• [Presentation] Beta7 integrin-mediated homing of exosomes to the gut (2017)
  • Author(s): 朴 恩正、Onmanee Prajuabjinda, Zay Yar Soe, 川本 英嗣、島岡 要
  • Organizer: 第46回 日本免疫学会
• [Presentation] Cancer exosomes stimulate endothelial cell migration (2016)
  • Author(s): Prajuabjinda O, Soe ZY, Kawamoto E, Shimaoka M, Park EJ
  • Organizer: 20th World Congress on Clinical Nutrition
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2016-12-14
  • Int'l Joint Research