Identification of novel biomarkers for lymphangioleiomyomatosis from extracellular vesicles by comprehensive approach .

• Project/Area Number: 19K08642
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: NHO Kinki Chuo Chest Medical Center(Clinical Research Center)
• Principal Investigator: Takimoto Takayuki 独立行政法人国立病院機構近畿中央呼吸器センター, その他部局等, 内科医長 (60767854)
• Co-Investigator(Kenkyū-buntansha): 武田 吉人 大阪大学, 医学系研究科, 准教授 (40452388) ; 井上 義一 独立行政法人国立病院機構近畿中央呼吸器センター, 臨床研究センター, 臨床研究センター長 (90240895)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: リンパ脈管筋腫症 / LAM / バイオマーカー / 細胞外小胞 / プロテオミクス / miRNA / エクソソーム / 呼吸器難病

Outline of Research at the Start

リンパ脈管筋腫症（LAM）は平滑筋細胞様のLAM細胞が増殖、肺に転移し、多発性嚢胞を形成する希少難病である。この難病の克服には病態解明や診断・治療法開発の観点から新たなバイオマーカー（BM）の開発が急務である。本研究では、最先端の技術（細胞外小胞・プロテオミクス技術・バイオインフォマティクス）を駆使し、多様な検体(血液・肺組織・肺胞洗浄液・LAM細胞)から得られたマルチオミックスデータの統合解析という包括的アプローチにより、LAMの病態解明からBMの開発に挑む。

Outline of Final Research Achievements

Lymphangioleiomyomatosis (LAM) is a rare and progressive cystic lung disease, which is intrinsically caused by the proliferation of so-called 'LAM cells'. In the current project, we focused on extracellular vesicles derived from patients’ blood and LAM cell lines to identify novel biomarkers for lymphangioleiomyomatosis in a comprehensive approach. Biomarker proteins were further validated in LAM lungs by Immunohistochemistry stains, and at least, four proteins were positively stained, suggesting derivation from the LAM cells in the lung.

Academic Significance and Societal Importance of the Research Achievements

LAMは難病ではあるが、希少疾患のため研究助成や研究者が少ないのが現状である。本研究では、LAMの新たな診断バイオマーカーを絞り込むことができた。これらの成果は、LAMの診断に寄与し、将来の治療法開発につながる可能性がある。

Research Products

• [Journal Article] CD14 and lipopolysaccharide-binding protein as novel biomarkers for sarcoidosis by proteomics of serum extracellular vesicles. (2022)
  • Author(s): Futami Y, Takeda Y, KobaT, Narumi R, Nojima Y, Ito M, Nakayama M, Ishida M,Yoshimura H, Naito Y, Fukushima K, Takimoto T, Edahiro R, Matsuki T, Nojima S, Hirata H, Koyama S, Iwahori K, Nagatomo I, Shirai Y, Suga Y, Satoh S, Futami S, Miyake K, Shiroyama T, Inoue Y, Adachi J, Tomonaga T, Ueda K, Kumanogoh A.
  • Journal Title: International immunology Volume: - Issue: 6 Pages: 1-1
  • DOI: 10.1093/intimm/dxac009
  • Peer Reviewed / Open Access
• [Journal Article] Proteomics of serum extracellular vesicles identifies a novel COPD biomarker, fibulin-3 from elastic fibres. (2021)
  • Author(s): Koba, Takeda, Narumi, Shiromizu, Nojima, Ito, Kuroyama, Futami, Takimoto, Matsuki, Edahiro, Nojima, Hayama, Fukushima, Hirata, Koyama, Iwahori, Nagatomo, Suzuki, Shirai, Murakami, Nakanishi, Nakatani, Suga, Miyake, Shiroyama, Kida, Sasaki, Ueda, Mizuguchi, Adachi, Tomonaga, Kumanogoh
  • Journal Title: ERJ open research. Volume: 7(1) Issue: 1 Pages: 00658-2020
  • DOI: 10.1183/23120541.00658-2020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diffuse Pulmonary Cysts in Metastatic Angiosarcoma (2020)
  • Author(s): Takimoto T, Osa A, Morita S, Abe K.
  • Journal Title: Internal Medicine Volume: 59 Issue: 3 Pages: 457-458
  • DOI: 10.2169/internalmedicine.3644-19
  • NAID: 130007793893
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-02-01
  • Peer Reviewed / Open Access
• [Journal Article] A lung abscess caused by secondary syphilis - the utility of polymerase chain reaction techniques in transbronchial biopsy: a case report. (2019)
  • Author(s): Futami S, Takimoto T, Nakagami F, Satoh S, Hamaguchi M, Kuroyama M, Miyake K, Koyama S, Iwahori K, Hirata H, Nagatomo I, Takeda Y, Kida H, Kumanogoh A.
  • Journal Title: BMC Infect Dis. Volume: 19(1):598. Issue: 1 Pages: 598-598
  • DOI: 10.1186/s12879-019-4236-4
  • Peer Reviewed / Open Access
• [Journal Article] Integrin-independent support of cancer drug resistance by tetraspanin CD151 (2019)
  • Author(s): Hwang Soonyean、Takimoto Takayuki、Hemler Martin E.
  • Journal Title: Cellular and Molecular Life Sciences Volume: 76 Issue: 8 Pages: 1595-1604
  • DOI: 10.1007/s00018-019-03014-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Proteomic Profiling of Serum Exosomes to Identify Novel Biomarkers for Lymphangioleiomyomatosis (2019)
  • Author(s): Takayuki Takimoto
  • Organizer: 2019 International Conference of the American Thoracic Society
  • Int'l Joint Research
• [Presentation] エクソソームのプロテオミクスによるリンパ脈管筋腫症のバイオマーカー探索 (2019)
  • Author(s): 滝本 宜之
  • Organizer: 第93回閉塞性肺疾患研究会