Study for the mechanism of mitochondrial-nuclear compatibility and the development of therapeutic methods
| Project/Area Number |
17K11248
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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 |
Obstetrics and gynecology
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| Research Institution | Jichi Medical University |
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Principal Investigator |
Endo Hitoshi 自治医科大学, 医学部, 教授 (50221817)
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| Project Period (FY) |
2017-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
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: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | ミトコンドリア / 遺伝子治療 / ミトコンドリア遺伝子異常 / ヘテロプラスミー / ゲノム編集 / ミトコンドリア適合性 / TALEN / 核ーミトコンドリア適合性 / 遺伝子 / 生殖医学 |
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| Outline of Final Research Achievements |
Mitochondrial DNA (mtDNA) is individually polymorphic. Recently, the mitochondrial transfer from other people to embryos has been reported in reproductive medicine, but there have been very few studies on the compatibility of mtDNA with nuclear genes. In this study, firstly, we originally generated conplastic mice with subspecies mtDNA in the same karyotype, established a disease mouse model with altered phenotype, and analyzed the pathogenesis. Secondly, we generated heteroplasmic ES cells with a mixture of both B6 and subspecies mtDNAs. Thirdly, we generated TALEN-modified vectors linked to mitochondrial proteins for optimization to mitochondrial targeting, and confirmed the effect of mitochondrial genome editing that specifically removes one mtDNA.
In conclusion, we generated a conplastic mouse model of nuclear-mitochondrial incompatibility showing exacerbation of the disease, and demonstrated that specific mtDNA can be removed by the TALEN using heteroplasmy model cells.
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| Academic Significance and Societal Importance of the Research Achievements |
近年、生殖医療において、ミトコンドリア遺伝子異常症の遺伝子治療法として受精卵への前核置換法が用られるが、二者のmtDNAが混在するヘテロプラスミーの状態となる。しかし、mtDNAと核遺伝子との適合性に関する研究は極めて少ない。本研究では、疾患モデルマウスをベースにした疾患コンプラステックマウスを作製し、ミトコンドリアと核の適合性により症状の変動を示したことは、学術的意義がある。また、mtDNAのヘテロプラスミーを解消する遺伝子治療法を開発することは非常に重要で社会的意義がある。複数のミトコンドリア標的シグナルおよびタンパク質を検討し、TALENのmtDNAへの標的を最適化した意義は大きい。
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Report
(5 results)
Research Products
(15 results)
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[Journal Article] Mesenchymal stromal cells inhibit aerobic glycolysis in activated T-cells by negatively regulating hexokinase II activity through PD-1/PD-L1 interaction.2021
Author(s)
Kawasaki, Y., Sato, K., Mashima, K., Nakano, H., Ikeda, T., Umino, K., Morita, K., Izawa, J., Takayama, N., Hayakawa, H., Tominaga, K., Endo, H., Kanda, Y.
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Journal Title
Biology of Blood and Marrow Transplantation
Volume: 27
Issue: 3
Pages: 231.e1-231.e8
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Comprehensive Metabolomic Analysis of IDH1(R132H) Clinical Glioma Samples Reveals Suppression of β-oxidation Due to Carnitine Deficiency.2019
Author(s)
Miyata S, Tominaga K*, Sakashita E, Urabe M, Onuki Y, Gomi A, Yamaguchi T, Mieno M, Mizukami H, Kume A, Ozawa K, Watanabe E, Kawai K, Endo H.
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Journal Title
Sci Rep.
Volume: 9
Issue: 1
Pages: 9787-9787
DOI
Related Report
Peer Reviewed / Open Access
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