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Application of innate immune cells and Spi-B (a trascription factor) to forensic pathology

Research Project

Project/Area Number 23K24624
Project/Area Number (Other) 22H03366 (2022-2023)
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeMulti-year Fund (2024)
Single-year Grants (2022-2023)
Section一般
Review Section Basic Section 58040:Forensics medicine-related
Research InstitutionWakayama Medical University

Principal Investigator

近藤 稔和  和歌山県立医科大学, 医学部, 教授 (70251923)

Project Period (FY) 2022-04-01 – 2026-03-31
Project Status Granted (Fiscal Year 2024)
Budget Amount *help
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2025: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2024: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2023: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Keywords分子法医病理学 / 分子法医診断学 / 自然免疫 / Spi-B / マクロファージ / 分子法医診断 / 心不全 / 動脈解離 / 法医診断学 / 心臓突然死 / マクロファージ・樹状細胞 / 遺伝子欠損 マウス / サイトカイン / ケモカイン / 病態モデル / 侵襲 / 樹状細胞
Outline of Research at the Start

自然免疫システムが様々な機械的・化学的侵襲及び内因性疾患においても活性化される.特に自然免疫担当細胞のマクロファージ・樹状細胞はHeterogeneityな細胞集団で,転写因子Spi-Bはこれらの細胞を機能の異なるサブセットに分化させるマスター因子の一つである.そこで,Spi-B遺伝子欠損マウスを用いて,種々の病態モデルにおけるSpi-Bの病態生理学的役割を検討し,病態特異的なSpi-B標的分子を探索し,マウス実験で得られた新規の候補分子については,実際の法医剖検試料を用いて検索し,その発現様式や発現量を各病態生理と有機的に関連付けることで,精度・客観性が高い分子法医診断学の確立を目指す.

Outline of Annual Research Achievements

1.心不全モデル:Spi-BはTACにより惹起される心不全の病態形成において炎症と線維化を抑制し保護的に機能することを明らかにした.また,その保護機能はLy-6c high,CCR2+マクロファージの心臓への遊走抑制による可能性が高いことを示す結果を得た.本年度は,Spi-BによるLy-6c high,CCR2+マクロファージの遊走の制御について更に検討を進めた.TAC初期の心臓におけるSpi-B発現とLy-6c high,CCR2+マクロファージ浸潤の経時的変化を解析すると,TAC後1日にどちらもピークを示し,両者の強い関連が明らかとなった.このことはTAC1日後に急激に増加し速やかに消失するLy-6c high,CCR2+マクロファージがSpi-B高発現細胞である可能性を示唆する.実際,FACS解析を行い,Ly-6c high,CCR2+マクロファージがSpi-Bを発現することを確認した.
2.大動脈解離マウス:前年度の研究で,アンギンテンシンⅡ(AngII)持続投与によりマウス大動脈解離モデルでSpi-Bが保護的に機能し,致死的な大動脈解離の発症を有意に抑制することを明かにしたが,本年度はその保護機構について解析を進めた.AngII持続投与マウスの大動脈における遺伝子発現を解析し,大動脈の細胞外マトリックスの安定化に必要なLysyl oxidase 1(Lox1)が野生型マウスにおいては発現が強く亢進したが,Spi-B-KOマウスではその発現亢進が有意に抑制されていることを明かにした.野生型とSpi-B-KOマウスにおけるLox1発現の相違は免疫組織染色でも確認された.このことはSpi-BがLox1発現を介して大動脈の安定化に寄与することを示唆し,AngII持続投与による大動脈解離の病態形成におけるSpi-Bの保護機構はLox1発現制御によることが明らかとなった.

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

おおむね順調に進展している.
TAC誘導心不全モデルにおいて心臓内マクロファージのサブセット組成が急激且つドラスティックに変化することが近年明らかにされているが,Spi-Bがそのサブセット組成変化に関与することを明らかにできた.特に単球由来のLy-6c high,CCR2+マクロファージにSpi-Bの発現を見出したことはSpi-Bの保護機構解析研究の方向性を示す重要な知見を得たものと考えている.一方,アンギンテンシンⅡ持続投与大動脈解離マウスモデルにおいては,Spi-Bの保護機構の鍵分子としてLox1を見出したことは今後の研究の進展を大きく加速するものと考えている.

Strategy for Future Research Activity

心不全モデルについては,Ly-6c high,CCR2+マクロファージの遊走を誘起するCCケモカインのSpi-Bによる発現制御を解析する.このことによって,Ly-6c high,CCR2+マクロファージ分化におけるSpi-Bがどのように関与するのかを分子レベルで解明する.さらに,剖検で採取された心臓におけるSpi-Bの発現態様を免疫組織学的に検索し,各事例における死因とSpi-Bの発現態様を解析することで,心臓突然死においてSpi-Bが有用な診断指標となるか否かについて検討する
大動脈解離モデルについては,Lox1とSpi-Bの発現細胞の同定とそれらの細胞の解離組織における出現の経時的変化について解析を進め,大動脈解離に特異的な細胞の同定とその機能,およびそれらに対するSpi-Bの関与を解明する.
その他,敗血症モデル,肝障害モデルの解析を進める.

Report

(2 results)
  • 2023 Annual Research Report
  • 2022 Annual Research Report
  • Research Products

    (39 results)

All 2024 2023 2022 Other

All Journal Article (15 results) (of which Int'l Joint Research: 15 results,  Peer Reviewed: 15 results,  Open Access: 12 results) Presentation (20 results) (of which Int'l Joint Research: 8 results,  Invited: 3 results) Book (1 results) Remarks (3 results)

  • [Journal Article] Forensic significance of intracardiac expressions of Nrf2 in acute myocardial ischemia2024

    • Author(s)
      Hiyamizu S, Ishida Y, Yasuda H, Kuninaka Y, Nosaka M, Ishigami A, Shimada E, Kimura A, Yamamoto H, Osako M, Zhang W, Goto U, Kamata T, Kondo T
    • Journal Title

      Scientific Reports

      Volume: 14 Issue: 1

    • DOI

      10.1038/s41598-024-54530-x

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Unveiling the Dark Nexus: A systematic review on the interplay of mental health, substance abuse, and socio-cultural factors in femicide2024

    • Author(s)
      Caroppo Emanuele、Sapienza Martina、Mazza Marianna、Sannella Alessandra、Cecchi Rossana、Marano Giuseppe、Kondo Toshikazu、Calabrese Carmela、De Lellis Pietro
    • Journal Title

      Legal Medicine

      Volume: 67 Pages: 102334-102334

    • DOI

      10.1016/j.legalmed.2023.102334

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A case of hemoperitoneum after percutaneous radiofrequency ablation in a patient with hepatocellular carcinoma2023

    • Author(s)
      Ishigami Akiko、Inaka Shogo、Ishida Yuko、Nosaka Mizuho、Kuninaka Yumi、Yamamoto Hiroki、Shimada Emi、Kimura Akihiko、Furukawa Fukumi、Kondo Toshikazu
    • Journal Title

      Forensic Science, Medicine and Pathology

      Volume: 20 Issue: 1 Pages: 189-193

    • DOI

      10.1007/s12024-023-00601-w

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] An autopsy case of fatal Japanese spotted fever in Wakayama2023

    • Author(s)
      Aragane M, Matsumoto L, Yasuda H, Nosaka M, Ishida Y, Yamamoto H, Kondo T, Ishigami A
    • Journal Title

      Legal medicine

      Volume: 66 Pages: 102355-102355

    • DOI

      10.1016/j.legalmed.2023.102355

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Malpratice claims in cardiology and cardiac surgery: A medico-legal issue2023

    • Author(s)
      Montisci R.、Licciardi M.、Cecchi R.、Kondo T.、Gerosa G.、Casula R.、Cecchetto G.、Montisci M.
    • Journal Title

      Legal Medicine

      Volume: 65 Pages: 102319-102319

    • DOI

      10.1016/j.legalmed.2023.102319

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Essential Involvement of Neutrophil Elastase in Acute Acetaminophen Hepatotoxicity Using BALB/c Mice2023

    • Author(s)
      Ishida Y, Zhang S, Kuninaka Y, Ishigami A, Nosaka M, Harie I, Kimura A, Mukaida N, Kondo T
    • Journal Title

      Int J Mol Sci

      Volume: 24 Issue: 9 Pages: 7845-7845

    • DOI

      10.3390/ijms24097845

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Forensic application of epidermal expression of HSP27 and HSP70 for the determination of wound vitality in human compressed neck skin2023

    • Author(s)
      Zhang S, Ishida Y, Ishigami A, Nosaka M, Kuninaka Y, Yasuda H, Kofuna A, Matsuki J, Osako M, Zhang W, Kimura A, Furukawa F, Kondo T
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1

    • DOI

      10.1038/s41598-023-33799-4

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Application and limitation of a biological clock-based method for estimating time of death in forensic practices2023

    • Author(s)
      Kimura Akihiko、Ishida Yuko、Nosaka Mizuho、Ishigami Akiko、Yamamoto Hiroki、Kuninaka Yumi、Hata Satoshi、Ozaki Mitsunori、Kondo Toshikazu
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1

    • DOI

      10.1038/s41598-023-33328-3

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Femicide and forensic pathology: Proposal for a shared medico-legal methodology2023

    • Author(s)
      Cecchi Rossana、Masotti Vittoria、Sassani Matilde、Sannella Alessandra、Agugiaro Giulia、Ikeda Tomoya、Pressanto Davide Maria、Caroppo Emanuele、Schirripa Maria Laura、Mazza Marianna、Kondo Toshikazu、De Lellis Pietro
    • Journal Title

      Legal Medicine

      Volume: 60 Pages: 102170-102170

    • DOI

      10.1016/j.legalmed.2022.102170

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Immune Mechanisms of Pulmonary Fibrosis with Bleomycin2023

    • Author(s)
      Ishida Yuko、Kuninaka Yumi、Mukaida Naofumi、Kondo Toshikazu
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 4 Pages: 3149-3149

    • DOI

      10.3390/ijms24043149

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] B cell receptor repertoire analysis from autopsy samples of COVID-19 patients2023

    • Author(s)
      Iwabuchi Sadahiro、Shichino Shigeyuki、Imafuku Tadashi、Yamaji Kenzaburo、Miyamoto Kyohei、Tamura Shinobu、Ueha Satoshi、Ito Toshihiro、Murata Shin-ichi、Kondo Toshikazu、Ikeo Kazuho、Suzuki Yutaka、Matsushima Kouji、Kohara Michinori、Torigoe Toshihiko、Yamaue Hiroki、Hashimoto Shinichi
    • Journal Title

      Frontiers in Immunology

      Volume: 14 Pages: 1034978-1034978

    • DOI

      10.3389/fimmu.2023.1034978

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Forensic application of aquaporins2023

    • Author(s)
      Ishida Y, Nosaka M, Ishigami A, Kondo T
    • Journal Title

      Legal Medicine

      Volume: 63 Pages: 102249-102249

    • DOI

      10.1016/j.legalmed.2023.102249

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Forensic Application of Epidermal Ubiquitin Expression to Determination of Wound Vitality in Human Compressed Neck Skin2022

    • Author(s)
      Zhang S, Ishida Y, Ishigami A, Nosaka M, Kuninaka Y, Hata S, Yamamoto H, Hashizume Y, Matsuki J, Yasuda H, Kimura A, Furukawa F, Kondo T
    • Journal Title

      Frontiers in Medicine

      Volume: 9

    • DOI

      10.3389/fmed.2022.867365

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A medico-legal definition of femicide2022

    • Author(s)
      Cecchi R.、Sassani M.、Agugiaro G.、Caroppo E.、De Lellis P.、Sannella A.、Mazza M.、Ikeda T.、Kondo T.、Masotti V.
    • Journal Title

      Legal Medicine

      Volume: 59 Pages: 102101-102101

    • DOI

      10.1016/j.legalmed.2022.102101

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Macrophage polarity and wound age determination2022

    • Author(s)
      Kuninaka Y, Ishida Y, Ishigami A, Nosaka M, Matsuki J, Yasuda H, Kofuna A, Kimura A, Furukawa F, Kondo T
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1

    • DOI

      10.1038/s41598-022-24577-9

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] The CCL3-CCR5 axis in Kupffer cells plays a detrimental role in acetaminophen-induced acute liver injury2023

    • Author(s)
      Ishida Y, Kuninaka Y, Nosaka M, Kimura A, Mukaida N, Kondo T
    • Organizer
      JSICR-MMCB2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Absence of CCL5/CCR5 axis exaggerates thrombus formation through reduced uPA, tPA and VEGF expression in murine DVT model2023

    • Author(s)
      Nosaka M, Ishida Y, Ishigami A, Kuninaka Y, Yamamoto H, Kimura A, Mukaida N, Kondo T
    • Organizer
      JSICR-MMCB2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Fractalkine/CX3CR1 axis contribute to renal fibrosis induced by unilateral ureteral obstruction2023

    • Author(s)
      Iwahashi Y, Ishida Y, Kuninaka Y, Ishigami A, Nosaka M, Kimura A, Mukaida N, Hara I, Kondo T
    • Organizer
      JSICR-MMCB2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 深部静脈血栓における熱ショック蛋白の動態と法医診断学的応用に関する研究(第2報)2023

    • Author(s)
      野坂みずほ,石田裕子,國中由美,石上安希子,山本寛記,大迫美優,島田栄美,川口真理子,木村章彦,近藤稔和
    • Organizer
      第107次日本法医学会学術全国集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Macrophage polarity and wound age determination2023

    • Author(s)
      石田裕子,國中由美,石上安希子,野坂みずほ,大迫美優,木村章彦,川口真理子,近藤稔和
    • Organizer
      第107次日本法医学会学術全国集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Forensic significance of intracardiac expressions of Nrf2 in acute myocardial ischemia2023

    • Author(s)
      冷水詩音,安田啓喜,石田裕子,國中由美,野坂みずほ,石上安希子,木村章彦,近藤稔和
    • Organizer
      第107次日本法医学会学術全国集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Crucial role of CX3CR1-CX3CL1 axis in thrombus resolution in murine DVT model2023

    • Author(s)
      Nosaka M, Ishida Y, Ishigami A, Kuninaka Y, Shimada E, Kawaguchi M, Kimura A, Mukaida N, Kondo T
    • Organizer
      ISTH 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 尿管結紮モデルマウスにおけるFractalkine/CX3CR1の分子病理学的役割の解明2023

    • Author(s)
      岩橋悠矢,石田裕子,國中由美,石上安希子,野坂みずほ,木村章彦,向田直史,原 勲,近藤稔和
    • Organizer
      第44回日本炎症・再生医学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Oncostatin M receptor β mediates skin wound healing by promoting fibroblast accumulation and function2023

    • Author(s)
      石田裕子,國中由美,小森忠祐,野坂みずほ,木村章彦,宮島 篤,森川吉博,川口真理子,近藤稔和
    • Organizer
      第44回日本炎症・再生医学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Spi-Bは圧負荷に対する心臓の代償応答過程においてマクロファージサブセットの構成を制御して抗炎症性に機能する2023

    • Author(s)
      近藤稔和,木村章彦,佐々木 泉,石田裕子,野坂みずほ,樽谷 玲,國中由美,加藤 喬,改正恒康
    • Organizer
      第44回日本炎症・再生医学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 乳幼児の突然死の手続きと死因究明2023

    • Author(s)
      近藤稔和
    • Organizer
      日本フォレンジック看護学会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Macrophage polarity and wound age determination2023

    • Author(s)
      T. Kondo, Y. Kuninaka, Y. Ishida, A. Ishigami, M. Nosaka, H. Yasuda, A. Kimura, F. Furukawa, M. Kawaguchi, H. Kinoshita
    • Organizer
      102. Jahrestagung der Deutschen Gesellschaft fuer Rechtsmedizin
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Crucial role of CX3CR1-CX3CL1 axis during thrombus resolution on stasis-induced murine deep vein thrombosis model2023

    • Author(s)
      Nosaka M, Ishida Y, Ishigami A, Kuninaka Y, Yamamoto H, Shimada E, Kawaguchi M, Kimura A, Mukaida N, Kondo T
    • Organizer
      Cytokines2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] CCL3-CCR5 axis in Kupffer cells plays a detrimental role in acetaminophen-induced acute liver injury2023

    • Author(s)
      Ishida Y, Kuninaka Y, Nosaka M, Kimura A, Mukaida N, Kawaguchi M, Kondo T.
    • Organizer
      Cytokines2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Fractalkine/CX3CR1 axis contribute to renal fibrosis induced by unilateral ureteral obstruction2023

    • Author(s)
      Iwahashi Y, Ishida Y, Kuninaka Y, Nosaka M, Kimura A, Mukaida N, Hara I, Kondo T
    • Organizer
      Cytokines2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] オンコスタチンM はMAP キナーゼ経路を介した線維芽細胞の活性化を通じて創傷治癒を促進する2023

    • Author(s)
      石田裕子,近藤稔和
    • Organizer
      第53回日本創傷治癒学会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] FORENSIC STUDY ON METHAMPHETAMINE-RELATED DEATHS2023

    • Author(s)
      Ohsako M, Yamamoto H, Takayasu T, Kawaguchi M, Ishida Y, Ishigami A, Nosaka M, Kuninaka Y, Yasuda Y, Kofuna A, Harie I, Kondo T.
    • Organizer
      The 47th Annual Fall Conference and Workshop of the Korean Society for Legal Medicine
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Absence of CCL5/CCR5 axis exaggerates thrombus formation through reduced uPA, tPA and VEGF2023

    • Author(s)
      Nosaka M, Ishida Y, Kuninaka Y, Ishigami A, Yamamoto H, Kimura A, Mukaida N, Kondo T
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Essential roles of the oncostatin M receptor β-mediated axis in skin wound healing by regulating HGF and TIMP-1 expression on fibroblasts2023

    • Author(s)
      Ishida Y, Kuninaka Y, Komori T, Nosaka M, Kimura A, Miyajima A, MorikawaY, Kawaguchi M, Kondo T
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] CCL3-CCR5 axis in Kupffer cells plays a detrimental role in acetaminophen-induced acute liver injury2023

    • Author(s)
      Kuninaka Y, Ishida Y, Nosaka M, Kimura A, Mukaida N, Kawaguchi M, Kondo T
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Book] Estimation of the Time Since Death2023

    • Author(s)
      Burkhard Madea
    • Total Pages
      397
    • Publisher
      CRC Press
    • ISBN
      9781032135533
    • Related Report
      2023 Annual Research Report
  • [Remarks] 早期心筋梗塞の新たな法医診断指標を発見、虚血関連分子Nrf2-和歌山医科大

    • URL

      https://www.qlifepro.com/news/20240404/nrf2-4.html

    • Related Report
      2023 Annual Research Report
  • [Remarks] Nrf2が早期心筋梗塞の法医診断に有用であることを解明

    • URL

      https://www.wakayama-med.ac.jp/intro/press/2024/2024-0328.html

    • Related Report
      2023 Annual Research Report
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Published: 2022-04-19   Modified: 2024-12-25  

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