The analysis of SSc pathogenesis utilizing 9 strains of new murine models

• Project/Area Number: 19H03680
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Tohoku University (2021); The University of Tokyo
• Principal Investigator: Asano Yoshihide 東北大学, 医学系研究科, 教授 (60313029)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 全身性強皮症 / 線維化 / 血管障害 / 免疫異常 / 転写因子FLI1 / 動物モデル / 新規強皮症モデルマウス / 転写因子Fli1 / B細胞 / マクロファージ / Fli1

Outline of Research at the Start

本研究では9系統の遺伝子改変マウスにおいて強皮症関連遺伝子の発現様式を経時的に解析し、強皮症の発症初期・進行期に活性化される遺伝子プログラムを臓器別・細胞別に明らかにする。その最終目標は、ヒト検体を用いた研究では解析困難な発症初期の強皮症の病態を、動物モデルを活用して解明し、「強皮症の病態解明および早期治療戦略の基盤となる病態概念の確立」を実現することである。

Outline of Final Research Achievements

This study was undertaken to investigate the gene program which is driven in the early stage of systemic sclerosis by using animal models with deficiency of Fli1 in various cell types. Major findings were as follows: (i) activated Fli1 +/- B cells produce excessive amount of IL-6 in the presence of macrophages through TLR9 stimulation, (ii) Fli1 deficiency increases the proportion of newly formed B cells, especially B-1a-like B cells, (iii) age-associated B cells are detected in splenic newly formed B cells. These results suggest that Fli1 deficiency is associated with the induction of B cell subset which likely plays a key role in early disease process of systemic sclerosis.

Academic Significance and Societal Importance of the Research Achievements

SScは緩徐に進行する希少疾患ゆえに、発症初期の病態を制御する遺伝子プログラムの同定は極めて困難であり、この点が早期例に対する治療戦略を確立するうえで大きな障害となっている。本研究は、複数のモデルマウスを活用してSScの発症初期の遺伝子プログラムの異常を同定することを目的として立案された。今回の検討により、SScの病態形成の初期に誘導される自己免疫の起源となるB細胞の形質変化が明らかとなった。今回同定したB細胞集団を対象にSSc関連転写因子ネットワークの同定を進め、SScの病態解明と新規治療薬開発の基盤となるデータの構築を進めていく予定である。

Research Products

• [Journal Article] Serum S100A12 levels: possible association with skin sclerosis and interstitial lung disease in systemic sclerosis. (2021)
  • Author(s): Omatsu J, Saigusa R, Miyagawa T, Fukui Y, Toyama S, Awaji K, Ikawa T, Norimatsu Y, Yoshizaki A, Sato S, Asano Y.
  • Journal Title: Exp Dermatol. Volume: 30 Issue: 3 Pages: 409-415
  • DOI: 10.1111/exd.14218
  • Peer Reviewed
• [Journal Article] Association of serum CXCL12 levels with arthropathy in patients with systemic sclerosis. (2021)
  • Author(s): Ikawa T, Miyagawa T, Fukui Y, Toyama S, Omatsu J, Awaji K, Norimatsu Y, Watanabe Y, Yoshizaki A, Sato S, Asano Y.
  • Journal Title: Int J Rheum Dis. Volume: 24 Issue: 2 Pages: 260-267
  • DOI: 10.1111/1756-185x.14037
  • Peer Reviewed
• [Journal Article] Serum vasohibin-1 levels: a potential marker of dermal and pulmonary fibrosis in systemic sclerosis. (2021)
  • Author(s): Yuki F, Nakamura K, Hirabayashi M, Miyagawa T, Toyama S, Omatsu J, Awaji K, Ikawa T, Norimatsu Y, Yoshizaki A, Sato S, Asano Y.
  • Journal Title: Exp Dermatol. Volume: ND Issue: 7 Pages: 951-958
  • DOI: 10.1111/exd.14321
  • Peer Reviewed
• [Journal Article] A potential contribution of decreased serum galectin-10 levels to systemic inflammation and pulmonary vascular involvement in systemic sclerosis. (2021)
  • Author(s): Awaji K, Miyagawa T, Fukui Y, Toyama S, Omatsu J, Norimatsu Y, Ikawa T, Watanabe Y, Yoshizaki A, Sato S, Asano Y.
  • Journal Title: Exp Dermatol. Volume: ND Issue: 7 Pages: 959-965
  • DOI: 10.1111/exd.14320
  • Peer Reviewed
• [Journal Article] Association of serum CCL20 levels with pulmonary vascular involvement and primary biliary cholangitis in patients with systemic sclerosis. (2021)
  • Author(s): Ikawa T, Miyagawa T, Fukui Y, Minatsuki S, Maki H, Inaba T, Hatano M, Toyama S, Omatsu J, Awaji K, Norimatsu Y, Watanabe Y, Yoshizaki A, Sato S, Asano Y.
  • Journal Title: Int J Rheum Dis. Volume: ND Issue: 5 Pages: 711-718
  • DOI: 10.1111/1756-185x.14103
  • Peer Reviewed
• [Journal Article] Serum levels of tissue factor pathway inhibitor: potential association with Raynaud’s phenomenon and telangiectasia in patients with systemic sclerosis. (2021)
  • Author(s): Norimatsu Y, Miyagawa T, Fukui Y, Omatsu J, Toyama S, Awaji K, Ikawa T, Watanabe Y, Yoshizaki A, Sato S, Asano Y.
  • Journal Title: J Dermatol. Volume: ND Issue: 8 Pages: 1253-1256
  • DOI: 10.1111/1346-8138.15893
  • Peer Reviewed
• [Journal Article] Regulation of skin fibrosis by RALDH1-producing dermal dendritic cells via retinoic acid-mediated regulatory T cell induction: A role in scleroderma (2020)
  • Author(s): Miura Shunsuke、Asano Yoshihide、Saigusa Ryosuke、Yamashita Takashi、Taniguchi Takashi、Takahashi Takehiro、Ichimura Yohei、Toyama Tetsuo、Yoshizaki Ayumi、Sato Shinichi、Kadono Takafumi
  • Journal Title: Journal of Dermatological Science Volume: 97 Issue: 2 Pages: 125-134
  • DOI: 10.1016/j.jdermsci.2020.01.002
  • Peer Reviewed
• [Journal Article] Decreased serum cathepsin S levels in patients with systemic sclerosis-associated interstitial lung disease. (2020)
  • Author(s): Toyama S, Yamashita T, Saigusa R, Miura S, Nakamura K, Hirabayashi M, Miyagawa T, Fukui Y, Omatsu J, Yoshizaki A, Sato S, Asano Y.
  • Journal Title: J Dermatol. Volume: 47 Issue: 9 Pages: 1027-1032
  • DOI: 10.1111/1346-8138.15458
  • Peer Reviewed
• [Journal Article] Altered properties of endothelial cells and mesenchymal stem cells underlying the development of scleroderma-like vasculopathy in Klf5+/- ;Fli1+/- mice. (2020)
  • Author(s): Nakamura K, Taniguchi T, Hirabayashi M, Yamashita T, Saigusa R, Miura S, Takahashi T, Toyama T, Ichimura Y, Yoshizaki A, Trojanowska M, Fujiu K, Nagai R, Sato S, Asano Y.
  • Journal Title: Arthritis Rheumatol. Volume: 72 Issue: 12 Pages: 2136-2146
  • DOI: 10.1002/art.41423
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fli1 deficiency induces endothelial adipsin expression, contributing to the onset of pulmonary arterial hypertension in systemic sclerosis (2019)
  • Author(s): Miyagawa Takuya、Taniguchi Takashi、Saigusa Ryosuke、Fukayama Maiko、Takahashi Takehiro、Yamashita Takashi、Hirabayashi Megumi、Miura Shunsuke、Nakamura Kouki、Yoshizaki Ayumi、Sato Shinichi、Asano Yoshihide
  • Journal Title: Rheumatology Volume: - Issue: 8 Pages: 2005-2015
  • DOI: 10.1093/rheumatology/kez517
  • Peer Reviewed
• [Journal Article] Unique correlation profile of adiponectin and retinol-binding protein 4 in patients with systemic sclerosis. (2019)
  • Author(s): Asano Y, Masui Y, Toyama T, Sato S.
  • Journal Title: J Dermatol. Volume: 46 Issue: 9 Pages: 819-820
  • DOI: 10.1111/1346-8138.14994
  • Peer Reviewed
• [Journal Article] Possible association of decreased serum CXCL 14 levels with digital ulcers in patients with systemic sclerosis (2019)
  • Author(s): Fukui Yuki、Miyagawa Takuya、Hirabayashi Megumi、Yamashita Takashi、Saigusa Ryosuke、Miura Shunsuke、Nakamura Kouki、Yoshizaki Ayumi、Sato Shinichi、Asano Yoshihide
  • Journal Title: The Journal of Dermatology Volume: 46 Issue: 7 Pages: 584-589
  • DOI: 10.1111/1346-8138.14914
• [Journal Article] Facile fabrication of PEG-coated PLGA microspheres via SPG membrane emulsification for the treatment of scleroderma by ECM degrading enzymes (2019)
  • Author(s): Ohta Seiichi、Matsuura Mai、Kawashima Yuta、Cai Xinyu、Taniguchi Machiko、Okochi Hitoshi、Asano Yoshihide、Sato Shinichi、Ito Taichi
  • Journal Title: Colloids and Surfaces B: Biointerfaces Volume: 179 Pages: 453-461
  • DOI: 10.1016/j.colsurfb.2019.04.028
  • Peer Reviewed
• [Journal Article] A potential contribution of decreased galectin-7 expression in stratified epithelia to the development of cutaneous and esophageal manifestations in systemic sclerosis. (2019)
  • Author(s): Saigusa R, Yamashita T, Miura S, Hirabayashi M, Nakamura K, Miyagawa T, Fukui Y, Yoshizaki A, Sato S, Asano Y.
  • Journal Title: Exp Dermatol. Volume: In press Issue: 5 Pages: 536-542
  • DOI: 10.1111/exd.13900
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A potential contribution of trappin-2 to the development of vasculopathy in systemic sclerosis. (2019)
  • Author(s): Miyagawa T, Asano Y, Saigusa R, Hirabayashi M, Yamashita T, Taniguchi T, Takahashi T, Nakamura K, Miura S, Yoshizaki A, Miyagaki T, Sato S.
  • Journal Title: J Eur Acad Dermatol Venereol. Volume: In press Issue: 4 Pages: 753-760
  • DOI: 10.1111/jdv.15387
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cyclophosphamide Pulse Therapy Normalizes Vascular Abnormalities in a Mouse Model of Systemic Sclerosis Vasculopathy (2019)
  • Author(s): Yamashita Takashi、Asano Yoshihide、Saigusa Ryosuke、Taniguchi Takashi、Hirabayashi Megumi、Miyagawa Takuya、Nakamura Kouki、Miura Shunsuke、Yoshizaki Ayumi、Trojanowska Maria、Sato Shinichi
  • Journal Title: Journal of Investigative Dermatology Volume: 139 Issue: 5 Pages: 1150-1160
  • DOI: 10.1016/j.jid.2018.11.016
• [Presentation] Myeloid cell-specific Fli1 knockout mice exhibit systemic sclerosis-like vasculopathy and delayed wound healing due to impaired vasculogenesis. (2019)
  • Author(s): Yuki Fukui, Takuya Miyagawa, Kouki Nakamura, Megumi Hirabayashi, Jun Omatsu, Satoshi Toyama, Ayumi Yoshizaki, Shinichi Sato, Yoshihide Asano.
  • Organizer: The 49th Annual ESDR Meeting 2019
  • Int'l Joint Research
• [Presentation] Vascular abnormalities in systemic sclerosis (2019)
  • Author(s): Yoshihide Asano
  • Organizer: 24th World Congress of Dermatology
  • Int'l Joint Research / Invited
• [Presentation] Skin research provides a window into new aspects of systemic disease pathogenesis (2019)
  • Author(s): Yoshihide Asano
  • Organizer: The 44th Annual Meeting of JSID
  • Int'l Joint Research / Invited