| ○種別 (必須): | □ | 学術論文 (審査論文)
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| ○言語 (必須): | □ | 英語
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| ○招待 (推奨): |
| ○審査 (推奨): | □ | Peer Review
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| ○カテゴリ (推奨): | □ | 研究
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| ○共著種別 (推奨): | □ | 国際共著 (徳島大学内研究者と国外研究機関所属研究者との共同研究)
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| ○著者 (必須): | 1. | (英) Chakraborty D (日) (読)
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| 2. | (英) Cui W (日) (読)
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| 3. | (英) Rosario GX (日) (読)
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| 4. | (英) Scott RL (日) (読)
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| 5. | (英) Dhakal P (日) (読)
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| 6. | (英) Renaud SJ (日) (読)
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| 7. | 立花 誠
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| 8. | (英) Rumi MAK (日) (読)
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| 9. | (英) Mason CW (日) (読)
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| 10. | (英) Krieg A (日) (読)
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| 11. | (英) Soares MJ (日) (読)
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| ○題名 (必須): | □ | (英) A HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia (日)
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| ○要約 (任意): | □ | (英) The hemochorial placenta develops from the coordinated multilineage differentiation of trophoblast stem (TS) cells. An invasive trophoblast cell lineage remodels uterine spiral arteries, facilitating nutrient flow, failure of which is associated with pathological conditions such as preeclampsia, intrauterine growth restriction, and preterm birth. Hypoxia plays an instructive role in influencing trophoblast cell differentiation and regulating placental organization. Key downstream hypoxia-activated events were delineated using rat TS cells and tested in vivo, using trophoblast-specific lentiviral gene delivery and genome editing. DNA microarray analyses performed on rat TS cells exposed to ambient or low oxygen and pregnant rats exposed to ambient or hypoxic conditions showed up-regulation of genes characteristic of an invasive/vascular remodeling/inflammatory phenotype. Among the shared up-regulated genes was matrix metallopeptidase 12 (MMP12). To explore the functional importance of MMP12 in trophoblast cell-directed spiral artery remodeling, we generated an Mmp12 mutant rat model using transcription activator-like nucleases-mediated genome editing. Homozygous mutant placentation sites showed decreased hypoxia-dependent endovascular trophoblast invasion and impaired trophoblast-directed spiral artery remodeling. A link was established between hypoxia/HIF and MMP12; however, evidence did not support Mmp12 as a direct target of HIF action. Lysine demethylase 3A (KDM3A) was identified as mediator of hypoxia/HIF regulation of Mmp12 Knockdown of KDM3A in rat TS cells inhibited the expression of a subset of the hypoxia-hypoxia inducible factor (HIF)-dependent transcripts, including Mmp12, altered H3K9 methylation status, and decreased hypoxia-induced trophoblast cell invasion in vitro and in vivo. The hypoxia-HIF-KDM3A-MMP12 regulatory circuit is conserved and facilitates placental adaptations to environmental challenges. (日)
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| ○キーワード (推奨): |
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| ○誌名 (必須): | □ | Proceedings of the National Academy of Sciences of the United States of America ([The National Academy of Sciences of the United States of America])
(pISSN: 0027-8424, eISSN: 1091-6490)
| ○ISSN (任意): | □ | 1091-6490
ISSN: 0027-8424
(pISSN: 0027-8424, eISSN: 1091-6490) Title: Proceedings of the National Academy of Sciences of the United States of AmericaTitle(ISO): Proc Natl Acad Sci U S APublisher: National Academy of Sciences (NLM Catalog)
(Scopus)
(CrossRef)
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| ○巻 (必須): | □ | 113
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| ○号 (必須): | □ | 46
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| ○頁 (必須): | □ | E7212 E7221
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| ○都市 (任意): |
| ○年月日 (必須): | □ | 西暦 2016年 12月 初日 (平成 28年 12月 初日)
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| ○URL (任意): |
| ○DOI (任意): | □ | 10.1073/pnas.1612626113 (→Scopusで検索)
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| ○PMID (任意): | □ | 27807143 (→Scopusで検索)
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| ○備考 (任意): | 1. | (英) Article.PublicationTypeList.PublicationType: Journal Article (日)
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| 2. | (英) KeywordList.Keyword: epigenetics (日)
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| 3. | (英) KeywordList.Keyword: hypoxia (日)
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| 4. | (英) KeywordList.Keyword: placenta (日)
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| 5. | (英) KeywordList.Keyword: plasticity (日)
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| 6. | (英) KeywordList.Keyword: trophoblast invasion (日)
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| 7. | (英) CoiStatement: The authors declare no conflict of interest. (日)
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