Molecular pathology for IPAS/HIF-3a gene SNP-mediated pulmonary hypertension in connective tissue disease
| Project/Area Number |
17K09964
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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 |
Collagenous pathology/Allergology
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| Research Institution | Asahikawa Medical College |
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Principal Investigator |
Makino Yuichi 旭川医科大学, 医学部, 教授 (90345033)
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| Co-Investigator(Kenkyū-buntansha) |
川口 鎮司 東京女子医科大学, 医学部, 准教授 (90297549)
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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 |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | HIF-3α / SNP / 標的遺伝子 / 低酸素応答 / 肺高血圧症 / 低酸素誘導性転写因子 / 一塩基多型 / ゲノム編集 / 膠原病 / 低酸素応答性転写因子 |
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| Outline of Final Research Achievements |
Pulmonary arterial hypertension (PAH) is a poor prognostic complication of connective tissue disease. We have identified non-synonymous single nucleotide polymorphisms (SNPs) of HIF3A gene in the patients with systemic sclerosis (SSc) associated with PAH. In this study, we aim to further investigate the pathophysiological roles of SNP-HIF3α to develop a novel therapeutic strategy targeting the hypoxia-inducible factors and the target genes. We found SSc-PAH related SNP-HIF3α is a potent transcriptional activator owing to a productive interaction with regulatory elements in addition to the hypoxia response element . Modulation of intermolecular interaction between HIF-3a and HIF-1b by the SNP seemed critical for the dysregulation of HIF-3 complex. On the other hand, we have generated gene-knockout mice by means of a genome editing. Analyses of the phenotype and adaptation capacity to the hypoxic environment of the mice are on the way.
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| Academic Significance and Societal Importance of the Research Achievements |
IPAS/HIF-3α遺伝子多型は転写因子としての機能を変化させ、従来未知の標的遺伝子の発現を増強させることが判明した。これらの遺伝子は強皮症の皮膚・肺病変の進展との関連が知られており、強皮症における肺高血圧症に密接に関わる可能性がある。IPAS/HIF-3α遺伝子多型とその標的遺伝子の解析により、強皮症における肺高血圧症のあらたな治療標的が提示されることが期待される。
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Report
(4 results)
Research Products
(1 results)
