Amendment of abnormal RasGRP signaling in patients with systemic autoimmunity

• Project/Area Number: 18K08380
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Tokyo Medical and Dental University (2019-2020); Hokkaido University (2018)
• Principal Investigator: Yasuda Shinsuke 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (00374231)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 関節リウマチ / 滑膜線維芽細胞 / RasGRP / 全身性エリテマトーデス / 細胞内シグナル / RasGRP1 / RasGRP4

Outline of Final Research Achievements

In the joints of patients with rheumatoid arthritis (RA), abnormal growth of synovial fibroblasts and secretion of cytokines as well as proteases contribute to cartilage and bone destruction. Although treatment strategy in RA has been dramatically improved, still half of the patients achieve remission and unwanted infections are induced by immunosuppression. In the current research program, we aimed to search for novel treatment strategy targeting RA-synovial fibroblasts. We found abnormally high expression of RasGRP2 and RasGRP4 in synovial fibroblasts derived from some of RA patients, which are signal molecules restrictively expressed in platelets and bone-marrow derived cells in normal state, respectively. RasGRP2 and 4 coordinately induce cell migration, proliferation and cytokine/protease production. Moreover, inhibition of RasGRP2/4 ameliorated arthritis and joint destruction in animal arthritis model.

Academic Significance and Societal Importance of the Research Achievements

RasGRPは1-4のファミリー分子からなるシグナル分子で、それぞれ血球の系統に比較的限局して発現する。関節リウマチの治療は飛躍的に進歩したが、寛解に至る患者は半数に過ぎず、免疫抑制に伴う感染症も避けがたい。本研究課題では、関節リウマチの本態とも言える増殖した滑膜においてRasGRP2,4が異所性発現すること、これらが共同して滑膜の病的な働きを促進すること、また関節炎動物モデルを用いてこれらが治療標的になり得ることを示した。これらは、RasGRP標的薬をリウマチの本態である滑膜にデリバリーする治療の開発に繋がる知見であるといえる。

Research Products

• [Int'l Joint Research] Harvard Medical School(米国)
• [Journal Article] MicroRNA-9 ameliorates destructive arthritis through down-regulation of NF-κB1-RANKL pathway in fibroblast-like synoviocytes (2020)
  • Author(s): Lee Wen Shi、Yasuda Shinsuke、Kono Michihiro、Kudo Yuki、Shimamura Sanae、Kono Michihito、Fujieda Yuichiro、Kato Masaru、Oku Kenji、Shimizu Tomohiro、Onodera Tomohiro、Iwasaki Norimasa、Atsumi Tatsuya
  • Journal Title: Clinical Immunology Volume: 212 Pages: 108348-108348
  • DOI: 10.1016/j.clim.2020.108348
  • Peer Reviewed
• [Journal Article] MicroRNA-9 ameliorates destructive arthritis through down-regulation of NF-κB1-RANKL pathway in fibroblast-like synoviocytes. (2020)
  • Author(s): Lee WS, Yasuda S, Kono M, Kudo Y, Shimamura S, Kono M, Fujieda Y, Kato M, Oku K, Shimizu T, Onodera T, Iwasaki N, Atsumi T
  • Journal Title: Clinical Immunology Volume: 212 Issue: 4 Pages: 108348-108348
  • DOI: 10.1007/s00774-020-01089-y
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RA滑膜における異所性RasGRP2の発現が破壊性関節炎に寄与する (2019)
  • Author(s): 保田晋助, 中村浩之, 嶋村抄苗
  • Journal Title: リウマチ科 Volume: 62 Pages: 375-380
• [Journal Article] Decreased expression of Serine/arginine-rich splicing factor 1 in T cells from patients with active systemic lupus erythematosus accounts for reduced expression of RasGRP1 and DNA methyltransferase 1 (2018)
  • Author(s): Kono M, Kurita T, Yasuda S, Kono M, Fujieda Y, Bohgaki T, Katsuyama T, Tsokos GC, Moulton VR, Atsumi T.
  • Journal Title: Arthritis Rheumatol Volume: 70 Issue: 12 Pages: 2046-2056
  • DOI: 10.1002/art.40585
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ectopic RASGRP2 (CalDAG-GEFI) Expression in Rheumatoid Synovium Contributes to the Development of Destructive Arthritis (2018)
  • Author(s): Nakamura H, Shimamura S, Yasuda S, Kono M, Kono M, Fujieda Y, Kato M, Oku K, Bohgaki T, Shimizu T, Iwasaki N, Atsumi T
  • Journal Title: Ann Rheum Dis Volume: 77 Issue: 1 Pages: 1765-1772
  • DOI: 10.1186/s13075-018-1647-3
  • Peer Reviewed
• [Presentation] Farnesyltransferase inhibitor suppresses the RasGRP4 and Ras interaction of fibroblast-like synoviocytes from patients with rheumatoid arthritis (2018)
  • Author(s): Shimamura S, Yasuda S, Kono Michihito, Fujieda Y, Kato M, Oku K, Bohgaki T, and Atsumi T
  • Organizer: 第47回日本免疫学会総会・学術集会
• [Presentation] 関節リウマチ患者に高発現したRasGRP2は線維芽細胞様滑膜細胞の接着および遊走に関与する (2018)
  • Author(s): 中村浩之、保田晋助、河野通大、嶋村抄苗、藤枝雄一郎、加藤将、奥健志、坊垣暁之、オルガアメングアル、渥美達也
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Presentation] Decreased expression of Serine/arginine-rich splicing factor 1 in T cells from patients with active systemic lupus erythematosus contributes to reduced expression of RasGRP1 (2018)
  • Author(s): Kono M, Kurita T, Yasuda S, Fujieda Y, Bohgaki T, Katsuyama T, Kono Michihito, Tsokos GC, Moulton VR, Atsumi T
  • Organizer: 第62回日本リウマチ学会学術集会
• [Presentation] Decreased expression of Serine/arginine-rich splicing factor 1 in T cells from patients with active systemic lupus erythematosus contributes to reduced expression of RasGRP1 (2018)
  • Author(s): Kono M, Kurita T, Yasuda S, Fujieda Y, Bohgaki T, Katsuyama T, Kono Michihito, Tsokos GC, Moulton VR, Atsumi T
  • Organizer: 11th International Congress on Autoimmunity
  • Int'l Joint Research
• [Presentation] RASGRP1 polymorphism can contribute to clinical manifestations in patients with systemic lupus erythematosus (2018)
  • Author(s): 14Kono M, Yasuda S, Kono Michihito, Fujieda Y, Kato M, Oku K, Bohgaki T, Atsumi T
  • Organizer: 20th Asia Pacific League of Associations for Rheumatology Congress
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 医薬用組成物 (2018)
  • Inventor(s): 保田晋助
  • Industrial Property Rights Holder: 国立大学法人北海道大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Acquisition Date: 2020
• [Patent(Industrial Property Rights)] 医薬用組成物 (2018)
  • Inventor(s): 保田晋助、中村浩之
  • Industrial Property Rights Holder: 国立大学法人北海道大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-138910
  • Filing Date: 2018