Elucidation of a novel defense mechanism mediated by PARD6B and its therapeutic application to inflammatory bowel disease

• Project/Area Number: 19K17486
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Nagoya University
• Principal Investigator: Maeda Keiko 名古屋大学, 医学部附属病院, 病院助教 (00830291)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 炎症性腸疾患 / 腸管上皮細胞 / 防御機構 / バリア機構 / エンドサイトーシス

Outline of Research at the Start

腸管上皮細胞は、病原体や腸内細菌に対する防御機構を持ち、その破綻は腸管感染症、炎症性腸疾患 (IBD)の進展に強く関与する。申請者らは、エンドサイトーシスを促進する新たな分子としてPARD6Bを同定した。さらに、腸管上皮細胞がPARD6Bの分解誘導を介して、エンドサイトーシスを阻害し、病原体の侵入を食い止めるという防御メカニズムを見出した。本研究では、1) PARD6Bの分解を誘導するシグナルの同定、2) 腸炎、IBDモデルマウスを用いた機能解析によるPARD6Bを介した防御機構の解明、3) IBD患者の予後予測マーカーとなりうるかの検証を行い、新たな治療ターゲットにつなげることを目的とする。

Outline of Final Research Achievements

Intestinal epithelial cells are constantly exposed to foreign antigens such as pathogens and have their own antigen recognition and defense mechanisms. In this study, we investigated what kind of signals induce PARD6B-mediated defense mechanisms in intestinal epithelial cells. Furthermore, we generated intestinal epithelial cell-specific PARD6B-deficient mice and analyzed the function of PARD6B. Intestinal epithelial cell-specific PARD6B-deficient mice showed decreased goblet cell number and exacerbated intestinal inflammation, suggesting that PARD6B is involved in goblet cell differentiation and regulation of intestinal inflammation.

Translated with www.DeepL.com/Translator (free version)

Academic Significance and Societal Importance of the Research Achievements

腸管上皮細胞がどのように病原体を認識して、感染を防御するかは不明な点が多かった。本研究において、腸管の上皮細胞が、病原体の細胞膜の糖脂質への結合を感知して、感染を防御することを発見した。病原体が細胞膜に結合すると、PARD6B/aPKC/Cdc42複合体の分解が誘導され、エンドソームの機能を阻害することにより、病原体の細胞内への侵入を阻止するという感染防御機構を同定した。この機構は、腸管感染症や炎症性腸疾患の病態に関与しており、本研究成果は、病態の解明につながることが期待される。

Research Products

• [Journal Article] Depletion of the apical endosome in response to viruses and bacterial toxins provides cell-autonomous host defense at mucosal surfaces (2022)
  • Author(s): Maeda K, Zachos NC, Orzalli MH, Schmieder SS, Chang D, Bugda Gwilt K, Doucet M, Baetz NW, Lee S, Crawford SE, Estes MK, Kagan JC, Turner JR, Lencer WI
  • Journal Title: Cell Host Microbe. Volume: 30 (2) Issue: 2 Pages: 216-231
  • DOI: 10.1016/j.chom.2021.12.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Gelsolin as a Potential Biomarker for Endoscopic Activity and Mucosal Healing in Ulcerative Colitis (2022)
  • Author(s): Maeda K, Nakamura M, Yamamura T, Sawada T, Ishikawa E, Oishi A, Ikegami S, Kakushima N, Furukawa K, Iida T, Mizutani Y, Ishikawa T, Ohno E, Honda T, Ishigami M, Kawashima H
  • Journal Title: Biomedicines Volume: 10(4) Issue: 4 Pages: 867-872
  • DOI: 10.3390/biomedicines10040872
  • Peer Reviewed / Open Access
• [Journal Article] Accuracy of Serum Leucine-Rich Alpha-2 Glycoprotein in Evaluating Endoscopic Disease Activity in Crohn's Disease (2022)
  • Author(s): Kawamura T, Yamamura T, Nakamura M, Maeda K, Sawada T, Ishikawa E, Iida T, Mizutani Y, Ishikawa T, Kakushima N, Furukawa K, Ohno E, Honda T, Kawashima H, Ishigami M
  • Journal Title: Inflamm Bowel Dis Volume: - Issue: 2 Pages: 245-253
  • DOI: 10.1093/ibd/izac076
  • Peer Reviewed
• [Journal Article] Preliminary Comparison of Endoscopic Brush and Net Catheters as the Sampling Tool to Analyze the Intestinal Mucus in the Rectum with Ulcerative Colitis Patients (2022)
  • Author(s): Nakamura M, Maeda K, Yamamoto K, Yamamura T, Sawada T, Ishikawa E, Kakushima N, Furukawa K, Iida T, Mizutani Y, Ishikawa T, Ohno E, Honda T, Ishigami M, Kawashima H.
  • Journal Title: Digestion Volume: 103 (3) Issue: 3 Pages: 232-243
  • DOI: 10.1159/000521929
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic yield of colon capsule endoscopy for Crohn’s disease lesions in the whole gastrointestinal tract (2021)
  • Author(s): Yamada Keisaku、Nakamura Masanao、Yamamura Takeshi、Maeda Keiko、Sawada Tsunaki、Mizutani Yasuyuki、Ishikawa Eri、Ishikawa Takuya、Kakushima Naomi、Furukawa Kazuhiro、Ohno Eizaburo、Kawashima Hiroki、Honda Takashi、Ishigami Masatoshi、Fujishiro Mitsuhiro
  • Journal Title: BMC Gastroenterology Volume: 21 Issue: 1
  • DOI: 10.1186/s12876-021-01657-0
  • Peer Reviewed
• [Journal Article] Detection of colorectal neoplasms using linked color imaging: A prospective, randomized, tandem colonoscopy trial (2021)
  • Author(s): Hasegawa Issei、Yamamura Takeshi、Suzuki Hiroto、Maeda Keiko、Sawada Tsunaki、Mizutani Yasuyuki、Ishikawa Eri、Ishikawa Takuya、Kakushima Naomi、Furukawa Kazuhiro、Ohno Eizaburo、Kawashima Hiroki、Nakamura Masanao、Fujishiro Mitsuhiro
  • Journal Title: Clinical Gastroenterology and Hepatology Volume: ー Issue: 8 Pages: 1708-1716.e4
  • DOI: 10.1016/j.cgh.2021.04.004
  • NAID: 120007190667
  • Peer Reviewed
• [Journal Article] Endoscopic Activity and Serum TNF-α Level at Baseline Are Associated With Clinical Response to Ustekinumab in Crohn’s Disease Patients (2020)
  • Author(s): Murate Kentaro、Maeda Keiko、Nakamura Masanao、Sugiyama Daisuke、Wada Hirotaka、Yamamura Takeshi、Sawada Tsunaki、Mizutani Yasuyuki、Ishikawa Takuya、Furukawa Kazuhiro、Ohno Eizaburo、Honda Takashi、Kawashima Hiroki、Miyahara Ryoji、Ishigami Masatoshi、Nishikawa Hiroyoshi、Fujishiro Mitsuhiro
  • Journal Title: Inflammatory Bowel Diseases Volume: 26 Issue: 11 Pages: 1669-1681
  • DOI: 10.1093/ibd/izaa086
  • Peer Reviewed
• [Journal Article] Filtrated Adipose Tissue-Derived Mesenchymal Stem Cell Lysate Ameliorates Experimental Acute Colitis in Mice (2020)
  • Author(s): Nishikawa Takahiro、Maeda Keiko、Nakamura Masanao、Yamamura Takeshi、Sawada Tsunaki、Mizutani Yasuyuki、Ito Takanori、Ishikawa Takuya、Furukawa Kazuhiro、Ohno Eizaburo、Miyahara Ryoji、Kawashima Hiroki、Honda Takashi、Ishigami Masatoshi、Yamamoto Tokunori、Matsumoto Seiji、Hotta Yuji、Fujishiro Mitsuhiro
  • Journal Title: Digestive Diseases and Sciences Volume: 66 Issue: 4 Pages: 1034-1044
  • DOI: 10.1007/s10620-020-06359-3
  • Peer Reviewed
• [Journal Article] Ustekinumab is effective against small bowel lesions in Crohn’s disease: two case reports (2020)
  • Author(s): Murate Kentaro、Nakamura Masanao、Yamamura Takeshi、Maeda Keiko、Sawada Tsunaki、Mizutani Yasuyuki、Ishikawa Eri、Kakushima Naomi、Furukawa Kazuhiro、Ohno Eizaburo、Honda Takashi、Kawashima Hiroki、Ishigami Masatoshi、Fujishiro Mitsuhiro
  • Journal Title: Clinical Journal of Gastroenterology Volume: 14 Issue: 1 Pages: 129-135
  • DOI: 10.1007/s12328-020-01242-0
• [Journal Article] Clinical Factors Associated With Missing Colorectal Polyp on Colon Capsule Endoscopy (2019)
  • Author(s): Keisaku Yamada 1, Masanao Nakamura 2, Takeshi Yamamura 3, Keiko Maeda 3, Tsunaki Sawada 3, Yasuyuki Mizutani 1, Takuya Ishikawa 1, Kazuhiro Furukawa 1, Eizaburo Ohno 1, Ryoji Miyahara 1, Hiroki Kawashima 1, Naoki Hotta 4, Yoshiki Hirooka 3
  • Journal Title: Digestion Volume: 5 Issue: 3 Pages: 1-7
  • DOI: 10.1159/000498942
  • Peer Reviewed
• [Journal Article] Lewis Score on Capsule Endoscopy as a Predictor of the Risk for Crohn's Disease-Related Emergency Hospitalization and Clinical Relapse in Patients With Small Bowel Crohn's Disease (2019)
  • Author(s): Nishikawa T, Nakamura M, Yamamura T, Maeda K, Sawada T, Mizutani Y, Ishikawa T, Furukawa K, Ohno E, Miyahara R, Kawashima H, Hirooka Y
  • Journal Title: Gastroenterol Res Pract Volume: 3 Pages: 425-427
  • Peer Reviewed
• [Presentation] PARD6B REGULATES INTESTINAL BARRIER FUNCTION IN INFLAMMATORY BOWEL DISEASE (2020)
  • Author(s): 前田啓子、中村正直、藤城光弘
  • Organizer: アメリカ消化器病週間
  • Int'l Joint Research
• [Presentation] PARD6B regulates intestinal barrier function in inflammatory bowel disease (2020)
  • Author(s): Keiko Maeda, Masanao Nakamura, Mitsuhiro Fujishiro
  • Organizer: DDW
  • Int'l Joint Research
• [Presentation] PARD6Bによる腸管上皮細胞の新たな防御機構の同定 (2019)
  • Author(s): 前田啓子、中村正直、藤城光弘
  • Organizer: 日本消化器病学会