Gene dysregulation by single nucleotide polymorphism of hypoxia-inducible transcription factor in molecular pathology of pulmonary hypertension

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08793
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Asahikawa Medical College
• Principal Investigator: Makino Yuichi 旭川医科大学, 医学部, 教授 (90345033)
• Co-Investigator(Kenkyū-buntansha): 川口 鎮司 東京女子医科大学, 医学部, 臨床教授 (90297549)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 肺高血圧症 / 低酸素応答性転写因子 / 遺伝子転写制御 / ゲノム編集法 / 遺伝子破壊動物

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-HIF3αpotentially activates transcription of inflammation-related genes such encoding interluekins or matrix degradation enzymes in an oxygen concentration-independent manner. On the other hand, we have generated HIF3α gene disrupted mice by means of a genome editing. Those mice showed abnormal vascular and alveolar remodeling in the lung. Analyses of the phenotype and adaptation capacity to the hypoxic environment of the mice are on the way.

Free Research Field

内科、膠原病学

Academic Significance and Societal Importance of the Research Achievements

IPAS/HIF-3α遺伝子多型は、従来未知の標的遺伝子の発現制御にかかわることが判明した。これらの遺伝子は慢性炎症病態、組織線維化制御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。また、IPAS/HIF-3α遺伝子破壊マウスでは肺構造の異常が出現したことから、肺組織においては、IPAS/HIF-3αはこれまで未知の機能を有している可能性示唆された。IPAS/HIF-3α遺伝子とその標的遺伝子の解析により、膠原病性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。