Elucidation of the origin of blood coagulation factor VIII-producing cells for the development of new hemophilia treatment
| Project/Area Number |
18K08370
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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 54010:Hematology and medical oncology-related
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| Research Institution | Jichi Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
早川 盛禎 自治医科大学, 医学部, 講師 (30326847)
長尾 恭光 自治医科大学, 医学部, 准教授 (80303874)
鴨下 信彦 自治医科大学, 医学部, 講師 (90302603)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 血液凝固第VIII因子 / 血友病A / 再生医療 / 遺伝子治療 / 肝臓類洞内皮細胞 / 血友病 / 第VIII因子 |
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| Outline of Final Research Achievements |
Since coagulation factors are produced by hepatocytes, the coagulation factors in blood are decreased in cirrhosis. However, blood coagulation factor VIII (FVIII) is rather elevated. Here, we attempted to identify FVIII-producing cells by using knock-in mice in which FVIII-producing cells were observed as EGFP-expressing cells. EGFP-expressing FVIII-producing cells were found only in hepatic sinusoids. FVIII-producing cells had characteristics of lymphatic endothelial cells, including CD146, CD31, and Lyve1, but also expressed the platelet marker Clec-2. FVIII-producing cells in the fetal liver were observed from E12.5 and increased with development to the same level as in adult mice at birth. FVIII-conditional deficient mice showed reduced FVIII levels when crossed with Lyve1-Cre mice. Finally, the AAV vector could efficiently express the reporter gene in FVIII-producing cells.
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| Academic Significance and Societal Importance of the Research Achievements |
これまでFVIIIの産生細胞について一貫した報告はなかった。本研究でFVIIIは臓器の中でも肝臓のみに発現し、かつ類洞内皮細胞の一部がFVIII産生を担っていることを明らかとした。さらに、FVIII産生細胞はリンパ管内皮細胞と同様の性質を有するが、特徴的な表面マーカーとして血小板に存在するClec-2を同定した。さらに、FVIII産生細胞の分化過程を明らかにし、発現が上昇する分子からFVIII産生細胞に遺伝子導入が可能なプロモーター領域を見出した。これらの研究成果は、FVIIIが遺伝的に欠損する血友病Aに対する新たな遺伝子治療、細胞治療に結びつくことが期待される。
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Report
(4 results)
Research Products
(35 results)
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[Journal Article] 血友病の遺伝子治療2018
Author(s)
大森 司
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Journal Title
Japanese Journal of Thrombosis and Hemostasis
Volume: 29
Issue: 6
Pages: 760-764
DOI
NAID
ISSN
0915-7441, 1880-8808
Related Report
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[Presentation] Adeno-associated virus vector based on serotype 3 represents an alternative serotype for hemophilia gene therapy2019
Author(s)
Ohmori, T., Mizukami, H., Hishikawa, S., Nakamura, H., Katakai, Y., Muramatsu, S., Ozawa, K., and Sakata, Y.
Organizer
Congress The International Society on Thrombosis and Haemostasis
Related Report
Int'l Joint Research
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