Circulating monocytes in contributing to myocardial involvement of systemic sclerosis
| Project/Area Number |
20K08812
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 54020:Connective tissue disease and allergy-related
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| Research Institution | Nippon Medical School |
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Principal Investigator |
Kuwana Masataka 日本医科大学, 大学院医学研究科, 大学院教授 (50245479)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 全身性強皮症 / バイオインフォマティクス / 心筋 / 強皮症 / 心筋炎 / 単球 / マクロファージ |
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| Outline of Research at the Start |
全身性強皮症(SSc)の病態として血管障害→慢性炎症→線維化のプロセスが示されている。申請者はこれまでSScの病態プロセスをつなぐmajor playerとして単球マクロファージに着目し、患者検体やモデルマウスを用いてその役割を実証してきた。本研究では、これまでの成果から「継続的な心筋の虚血・再潅流傷害に対して骨髄から動員された心筋指向性単球が心筋にリクルートされ、線維化を促進することでSScに特徴的な心筋病変を形成する」という仮説をたて、in vitro/in vivo実験系を用いて検証する。本研究は学術的独自性が高く、その成果は心病変のバイオマーカー、新たな治療法の開発に資する。
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| Outline of Final Research Achievements |
The heart involvement in systemic sclerosis (SSc) is a poor prognostic factor, although the detailed pathogenesis remains unclear. We conducted transcriptomic analysis of myocardial tissue samples obtained by endomyocardial biopsy from SSc patients with primary heart involvement. Compared to the control group (dilated cardiomyopathy), the SSc myocardium showed activation of pathways related to myocardial energy metabolism, such as fatty acid beta-oxidation and the citric acid cycle, and upstream regulators including NUPR1 and IL-1β were predicted to be activated, leading to dysregulation of microtubules and cytoskeleton of the heart. Estimation of immune cell population did not show any significant differences in the number of specific cell types or oligoclonality compared with the control. These findings suggests that SSc myocardium have a distinct molecular pathogenesis compared to dilated cardiomyopathy.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究はSSc患者心筋を用いた初めてのトランスクリプトーム解析である。症例数が少ない、対照が健常心筋ではなく拡張型心筋症患者の心筋であるなど制約があるものの、仮説なしの網羅的解析により病態と関連するパスウェイや上流制御因子が同定された学術的意義は大きい。本研究成果は難治性病態の解明に役立つとともに、新たに同定された治療標的に対する新規治療薬の開発につながる可能性を秘めている。
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Report
(4 results)
Research Products
(17 results)
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[Journal Article] Initial predictors of skin thickness progression in patients with diffuse cutaneous systemic sclerosis: results from a multicentre prospective cohort in Japan.2021
Author(s)
Kuwana M, Hasegawa M, Fukue R, Shirai Y, Ishikawa O, Endo H, Ogawa F, Goto D, Kawaguchi Y, Sato S, Ihn H, and Takehara K
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Journal Title
Mod. Rheumatol
Volume: 31(2)
Issue: 2
Pages: 386-393
DOI
Related Report
Peer Reviewed
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[Journal Article] A randomized, double-blind, placebo-controlled phase 3 study of lenabasum in diffuse cutaneous systemic sclerosis: RESOLVE-1 design and rationale2021
Author(s)
Spiera R, Khanna D, Kuwana M, Furst DE, Frech TM, Hummers L, Stevens W, Matucci-Cerinic M, Baron M, Distler O, Dgetluck N, Bloom BJ, Dinh Q, White B, and Denton CP
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Journal Title
Clin. Exp. Rheumatol
Volume: 131
Pages: 124-133
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Nintedanib in patients with systemic sclerosis-associated interstitial lung disease: subgroup analyses by autoantibody status and skin score.2021
Author(s)
Kuwana M, Allanore Y, Denton CP, Distler JHW, Steen VD, Khanna D, Matucci-Cerinic M, Mayes MD, Volkmann ER, Miede C, Gahlemann M, Quaresma Lic M, Alves M, and Distler O
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Journal Title
Arthritis Rheumatol
Volume: 74
Issue: 3
Pages: 518-526
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Systemic sclerosis and the COVID-19 pandemic: World Scleroderma Foundation preliminary advice for patient management2020
Author(s)
Matucci-Cerinic M, Bruni C, Allanore Y, Clementi M, Dagna L, Damjanov N, De Paulis A, Denton CP, Distler O, Fox D, Furst DE, Khanna D, Krieg T, Kuwana M, Lee EB, Li, Pillai S, Wang Y, Zeng X, and Taliani G
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Journal Title
Ann. Rheum. Dis
Volume: 79(6)
Issue: 6
Pages: 724-726
DOI
Related Report
Peer Reviewed
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