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Prevention of CaCl2-induced aortic inflammation and subsequent aneurysm formation by the CCL3–CCR5 axis

Research Project

Project/Area Number 20H03957
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 58040:Forensics medicine-related
Research InstitutionWakayama Medical University

Principal Investigator

Ishida Yuko  和歌山県立医科大学, 医学部, 准教授 (10364077)

Co-Investigator(Kenkyū-buntansha) 野坂 みずほ  和歌山県立医科大学, 医学部, 講師 (00244731)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2023: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2022: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2021: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2020: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
Keywords大動脈瘤 / 突然死 / ケモカイン / マウス / 分子機序
Outline of Research at the Start

腹部大動脈瘤動物モデルを用いて,大動脈瘤の病態形成過程においてkey playerとなるケモカイン及びケモカイン受容体の発現動態と病態形成との関係性を明らかにする.その結果に基づいて,実際の法医剖検例において採取した各種臓器におけるケモカイン及びケモカイン受容体の動態を検討する.最終的には,ケモカインシステムが動脈瘤を起因とする突然死における死因判定の有用な分子指標の一つとなり得るか否かについて検討し,病態生理学に基づく分子生物学的法医診断法の確立を目指す.

Outline of Final Research Achievements

We report that CaCl2 application into abdominal aorta induces abdominal aortic aneurysm (AAA) with intra-aortic infiltration of macrophages as well as enhanced expression of CCL3 and MMP-9. Moreover, infiltrating macrophages express CCR5 and MMP-9. Both Ccl3-/- mice and Ccr5-/- but not Ccr1-/- mice exhibit exaggerated CaCl2-inducced AAA with augmented macrophage infiltration and MMP-9 expression. Immunoneutralization of CCL3 mimics the phenotypes observed in CaCl2-treated Ccl3-/- mice. On the contrary, CCL3 treatment attenuates CaCl2-induced AAA in both wild-type and Ccl3-/- mice. Consistently, we find that the CCL3-CCR5 axis suppresses PMA-induced enhancement of MMP-9 expression in macrophages. Thus, CCL3 can be effective to prevent the development of CaCl2-induced AAA by suppressing MMP-9 expression.

Academic Significance and Societal Importance of the Research Achievements

我々の実験的研究は、CCL3-CCR5経路がAAA形成において保護的な役割を果たしていることを示している。白人のかなりの割合がヒトCCR5遺伝子にΔ32と呼ばれる32塩基対の欠失対立遺伝子を有しており、CCR5 Δ32変異を持つホモ接合体は、Ccr5-/-マウスと同様に機能的なCCR5タンパク質を発現しない。CCR5 Δ32変異はAAAの発症率を増加させたが、これはCaCl2-あるいはAngiotensin IIで処理したCcr5-/-マウスにおける我々の観察と一致していた。したがって、動脈瘤に対するCCL3の治療活性を検討することは妥当である。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (3 results)

All 2022 2021

All Presentation (3 results) (of which Int'l Joint Research: 2 results)

  • [Presentation] Prevention of CaCl2-induced aortic inflammation and subsequent aneurysm formation by CCL32022

    • Author(s)
      石田裕子
    • Organizer
      第106次日本法医学会学術全国集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Prevention of CaCl2-induced aortic inflammation and subsequent aneurysm formation by CCL32021

    • Author(s)
      Yuko Ishida
    • Organizer
      MMCB2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Prevention of CaCl2-induced aortic inflammation and subsequent aneurysm formation by CCL32021

    • Author(s)
      Yuko Ishida
    • Organizer
      Cytokines2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research

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Published: 2020-04-28   Modified: 2025-01-30  

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