| Project/Area Number |
17K08891
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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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| Research Field |
Immunology
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| Research Institution | Tokyo University of Science |
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Principal Investigator |
Mizuta Ryushin 東京理科大学, 研究推進機構生命医科学研究所, 教授 (50297628)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | DNase γ / DNase1L3 / CAD / ネクローシス / アポトーシス / cfDNA / NETS / liquide biopsy / DNaseγ / DNase I / liquid biopsy / DNaseⅠ / NET / DNase1l3 / DNase1 / 好中球 / 遺伝子 / 核酸 / 癌 / 細胞 / 免疫学 |
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| Outline of Final Research Achievements |
Cell-free DNA (cfDNA) (e.g. fetal- or tumor-derived DNA) is DNA found in the blood circulation. It is now widely investigated as a biomarker for prenatal screening, tumor diagnosis, and tumor monitoring as “liquid biopsies”. However, the biological and biochemical aspects of cfDNA remain unclear. Although cfDNA is considered to be mainly derived from dead cells, information is scarce as to whether it is apoptotic or necrotic and what kinds of endonucleases or DNases are involved. We induced in vivo hepatocyte necrosis and apoptosis in mice deficient in DNase γ (also named DNase1L3) and/or caspase-activated DNase (CAD) genes with acetaminophen overdose and anti-Fas antibody treatments. We found that (i) DNase γ was the endonuclease responsible for generating cfDNA in acetaminophen-induced hepatocyte necrosis and (ii) CAD and DNase γ cooperated in producing cfDNA for anti-Fas mediated hepatocyte apoptosis.
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| Academic Significance and Societal Importance of the Research Achievements |
２つのDNA切断酵素CADおよびDNaseγがcfDNA の生成に関与することが明らかになったことより、酵素の特異性をふまえたcfDNAの評価ならびに精製プロトコールの作製に寄与するものと期待される。また、DNaseγが血流中に漏出したDNAを最初に分解する酵素であることが明らかになったことより、DNAを骨格として形成された血栓の治療に有効であること、またそのような血栓を足場として広がるがん細胞の転移の抑制にも応用できる可能性が示唆された。
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