| Project/Area Number |
19K08611
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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 53030:Respiratory medicine-related
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| Research Institution | Juntendo University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | リンパ脈管筋腫症 / 細胞外小胞 / リンパ管新生 / mTORシグナル / 形質転換 |
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| Outline of Research at the Start |
リンパ脈管筋腫症（LAM）では、TSC遺伝子変異によるmTORの過剰な活性化がLAM細胞のクローナルな増殖を来たすことが病因と考えられてきた。しかし、LAM病巣内ではむしろTSC変異陰性LAM細胞が大部分を占めており、TSC変異陽性LAM細胞が何らかの手段により周辺細胞を形態学的・機能的に類似したLAM細胞様に変化させLAM病巣を形成すると考えられるようになった。申請者はTSC変異陽性LAM細胞からの細胞外小胞が病巣周辺のリンパ管内皮細胞や間葉系細胞をLAM細胞へ形質転換させて病巣を形成すると仮説をたて、それを検証するための研究を行う。
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| Outline of Final Research Achievements |
Chyle leak is a peculiar complication in lymphangioleiomyomatosis (LAM) and therefore must be precious material to elucidate pathobiology of LAM. We examined the exosomes obtained from serum and chylous pleural effusion (CPL) in patients with LAM. When fetal lung fibroblast cell line (HFL-1) were exposed with the exosomes from CPL (CPL-exosomes), we found the expression of NOTCH1 and RHEB mRNAs were upregulated about 1.5-2.0 fold. However, we could not demonstrate this upregulation in protein levels. Microarray analysis of miRNAs in CPL-exosomes revealed that the expression levels of 5 miRNAs (miR-21、miR-23a、miR-23b、miR-26、and miR-451a) were significantly decreased as compared with those in the exosomes from control chylous pleural effusions. However, this was not associated with the miRNAs levels in serum from LAM patients irrespective of during or before sirolimus treatment.
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| Academic Significance and Societal Importance of the Research Achievements |
患者診療により得られる病態解明への示唆や臨床検体を研究に生かし、「TSC変異陽性LAM細胞はEVsを分泌し周辺細胞にphenotype transferして病巣を形成する。このメカニズムを明らかにすれば、病態解明と新規治療の開発につながるのではないか？」という学術的問いを解明する、学術的および社会的意義のある研究である。
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