Functional analysis of Survivin splice variants in synovium of rheumatoid arthritis using genome editing

• Project/Area Number: 19K18499
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Hiroshima University
• Principal Investigator: Mokuda Sho 広島大学, 病院(医), 講師 (80837162)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Discontinued (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 関節リウマチ / 炎症 / 細胞増殖 / 滑膜線維芽細胞 / サバイビン / スプライスバリアント / ゲノム編集

Outline of Research at the Start

関節リウマチ(RA)は、骨・軟骨の破壊を伴う全身性の滑膜炎が主体となる自己免疫疾患である。RAの滑膜組織は病的な増殖能を持つが、これまでの研究からこの原因としてがん原遺伝子であるサバイビンの関与が想定された。サバイビンがRAにおいてどのような機能を有するのかを、ゲノム編集法CRISPR/Cas9を用いて遺伝子レベルで証明し、RAの滑膜増殖コントロールに有効な新規の治療標的を開発することを目指す。

Outline of Final Research Achievements

The applicants aimed to elucidate the proliferative potential of synovium in arthritis from the viewpoint of apoptosis, chemotaxis and its functional relationship with inflammation. They aimed to develop previously unidentified factors by comprehensive gene expression analysis using RNA-seq. In synovial fibroblasts stimulated by the proinflammatory cytokine IL-1β, they found decreased gene expression of apoptosis-promoting factors. It was also confirmed that blood coagulation Factor XIII increased the expression of apoptosis inhibitory factor and chemokine genes.

Academic Significance and Societal Importance of the Research Achievements

本研究は、関節リウマチ（RA）の病態の中心である関節滑膜・滑膜線維芽細胞について、病態の解明を目的とした研究である。RAにおける滑膜線維芽細胞の特徴として、炎症性サイトカインの産生能、及び、旺盛な増殖能が挙げられる。本研究で得られた結果は、その病態を分子生物学的に説明することを可能にしており、炎症に伴う滑膜増殖の分子メカニズムを表現することでRAの病態解明に寄与すると考えられた。

Research Products

• [Journal Article] Comment on: Combination of immunosuppressive therapy and nintedanib improves capillaroscopic changes in systemic sclerosis-interstitial lung disease: a case report (2022)
  • Author(s): Tomohiro Sugimoto, Yusuke Yoshida, Sho Mokuda, Shintaro Hirata
  • Journal Title: Rheumatol Adv Pract . Volume: 6 Issue: 1
  • DOI: 10.1093/rap/rkac024
  • Peer Reviewed / Open Access
• [Journal Article] Comment on: Nailfold capillaries and myositis-specific antibodies in anti-melanoma differentiation-associated gene 5 antibody-positive DM. Reply (2022)
  • Author(s): Tomohiro Sugimoto, Sho Mokuda, Hiroki Kohno, Michinori Ishitoku, Kei Araki, Hirofumi Watanabe, Tadahiro Tokunaga, Yusuke Yoshida, Shintaro Hirata, Eiji Sugiyama
  • Journal Title: Rheumatology (Oxford) . Volume: 61 Issue: 5 Pages: e122-e124
  • DOI: 10.1093/rheumatology/keab822
  • Peer Reviewed
• [Journal Article] The Lipopolysaccharide Mutant Re-LPS Is a Useful Tool for Detecting LPS Contamination in Rheumatoid Synovial Cell Cultures (2021)
  • Author(s): Kohno Hiroki、Ouhara Kazuhisa、Mokuda Sho、Tokunaga Tadahiro、Sugimoto Tomohiro、Watanabe Hirofumi、Ishitoku Michinori、Yoshida Yusuke、Mizuno Noriyoshi、Ozawa Tatsuhiko、Kawataka Masatoshi、Hirata Shintaro、Kishi Hiroyuki、Sugiyama Eiji
  • Journal Title: Pathobiology Volume: 89 Issue: 2 Pages: 92-100
  • DOI: 10.1159/000520022
  • Peer Reviewed
• [Journal Article] Nailfold capillaries and myositis specific antibodies in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis (2021)
  • Author(s): Sugimoto, T. Mokuda, S. Kohno, H. Ishitoku, M. Araki, K. Watanabe, H. Tokunaga, T. Yoshida, Y. Hirata, S. Sugiyama, E.
  • Journal Title: Rheumatology (Oxford) Volume: - Issue: 5 Pages: 2006-2015
  • DOI: 10.1093/rheumatology/keab681
  • Peer Reviewed
• [Journal Article] C-reactive protein and ground-glass opacity as predictors for intractable interstitial lung disease in patients with systemic sclerosis under cyclophosphamide treatment regardless of concomitant glucocorticoids (2021)
  • Author(s): Yusuke Yoshida, Tomohiro Sugimoto, Yohei Hosokawa, Harumichi Suma, Hiroki Kobayashi, Michinori Ishitoku, Hiroki Kohno, Tadahiro Tokunaga, Hirofumi Watanabe, Sho Mokuda, Takaki Nojima, Shintaro Hirata, Eiji Sugiyama
  • Journal Title: Modern Rheumatology Volume: ahead of print Issue: 1 Pages: 141-148
  • DOI: 10.1080/14397595.2021.1907014
  • Peer Reviewed
• [Journal Article] Tapering and discontinuation of oral glucocorticoids without deterioration of disease status in patients with rheumatoid arthritis under a stable treatment (2021)
  • Author(s): Shintaro Hirata, Hiroki Kohno, Hirofumi Watanabe, Tadahiro Tokunaga, Yusuke Yoshida, Tomohiro Sugimoto, Sho Mokuda, Keisuke Oda, Takaki Nojima, Eiji Sugiyama
  • Journal Title: Modern Rheumatology Volume: ahead of print Issue: 4 Pages: 803-808
  • DOI: 10.1080/14397595.2020.1864914
  • Peer Reviewed
• [Journal Article] Rapid changes of nailfold capillary abnormalities during treatment for a patient with dermatomyositis complicated by lung cancer: a case report (2021)
  • Author(s): Tomohiro Sugimoto, Sho Mokuda, Kakuhiro Yamaguchi, Kei Araki, Hiroki Kohno, Yusuke Yoshida, Shintaro Hirata, Noboru Hattori, Eiji Sugiyama
  • Journal Title: Modern Rheumatology Case Reports Volume: 5 Issue: 1 Pages: 95-100
  • DOI: 10.1080/24725625.2020.1826650
  • Peer Reviewed / Open Access
• [Journal Article] Asymptomatic coronary aneurysms in a patient with eosinophilic granulomatosis with polyangiitis who developed a digital gangrene (2021)
  • Author(s): Mayu Sato, Yusuke Yoshida, Tomohiro Sugimoto, Shinji Kishimoto, Takuji Omoto, Hirofumi Watanabe, Tadahiro Tokunaga, Kazutoshi Yukawa, Hiroki Kohno, Sho Mokuda, Takaki Nojima, Shintaro Hirata, Eiji Sugiyama
  • Journal Title: Modern Rheumatology Case Reports Volume: 5 Issue: 1 Pages: 130-136
  • DOI: 10.1080/24725625.2020.1810404
  • Peer Reviewed / Open Access
• [Journal Article] Lower CH50 as a predictor for intractable or recurrent lupus enteritis: A retrospective observational study (2021)
  • Author(s): Yusuke Yoshida, Takuji Omoto, Hiroki Kohno, Tadahiro Tokunaga, Tatsuomi Kuranobu, Kazutoshi Yukawa, Hirofumi Watanabe, Katsuhiro Oi, Tomohiro Sugimoto, Sho Mokuda, Takaki Nojima, Shintaro Hirata, Eiji Sugiyama
  • Journal Title: Modern Rheumatology Volume: 31 Issue: 3 Pages: 643-648
  • DOI: 10.1080/14397595.2020.1812871
  • Peer Reviewed
• [Journal Article] Angiotensin-converting Enzyme 2, a SARS-CoV-2 Receptor, Is Upregulated by Interleukin 6 through STAT3 Signaling in Synovial Tissues. (2020)
  • Author(s): Mokuda S, Tokunaga T, Masumoto J, Sugiyama E.
  • Journal Title: J Rheumatol. Volume: 47 Issue: 10 Pages: 2553-2558
  • DOI: 10.3899/jrheum.200547
  • Peer Reviewed / Open Access
• [Journal Article] Activin A Expressed in Rheumatoid Synovial Cells Downregulates TNFα-Induced CXCL10 Expression and Osteoclastogenesis (2020)
  • Author(s): Kuranobu T, Mokuda S, Oi K, Tokunaga T, Yukawa K, Kohno H, Yoshida Y, Hirata S, Sugiyama E
  • Journal Title: Pathobiology Volume: - Issue: 3 Pages: 198-207
  • DOI: 10.1159/000506260
  • Peer Reviewed
• [Journal Article] TGFβ1 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expression (2020)
  • Author(s): Tokunaga T, Mokuda S, Kohno H, Yukawa K, Kuranobu T, Oi K, Yoshida Y, Hirata S, Sugiyama E
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 3 Pages: 800-800
  • DOI: 10.3390/ijms21030800
  • Peer Reviewed / Open Access
• [Journal Article] Serum CXCL10 levels are associated with better responses to abatacept treatment of rheumatoid arthritis. (2020)
  • Author(s): Yukawa K, Mokuda S, Kohno H, Oi K, Kuranobu T, Tokunaga T, Yoshida Y, Yamana J, Iwahashi M, Hirata S, Yamana S, Sugiyama E.
  • Journal Title: Clinical and Experimental Rheumatology Volume: -
  • Peer Reviewed
• [Journal Article] Large-vessel vasculitis associated with PEGylated granulocyte-colony stimulating factor. (2019)
  • Author(s): Yukawa K, Mokuda S, Yoshida Y, Hirata S, Sugiyama E.
  • Journal Title: The Netherlands Journal of Medicine Volume: 77 Pages: 224-226
  • Peer Reviewed / Open Access
• [Journal Article] Wwp2 maintains cartilage homeostasis through regulation of Adamts5. (2019)
  • Author(s): Mokuda S, Nakamichi R, Matsuzaki T, Ito Y, Sato T, Miyata K, Inui M, Olmer M, Sugiyama E, Lotz M, Asahara H,
  • Journal Title: Nature Communications Volume: 10 Pages: 2429-2429
  • Peer Reviewed / Open Access / Int'l Joint Research