Inflammetory cytokines-induced HIF-1 activation confers the epithelial-to-mesenchymal cell differentiation in endometrial epithelial cells

Research Project

Project/Area Number	19K09766
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 56040:Obstetrics and gynecology-related
Research Institution	Kansai Medical University
Principal Investigator	NAKAO Tomoko 関西医科大学, 医学部, 講師 (00465642)
Co-Investigator(Kenkyū-buntansha)	岡田英孝関西医科大学, 医学部, 教授 (80330182)
Project Period (FY)	2019-04-01 – 2022-03-31
Project Status	Completed (Fiscal Year 2021)
Budget Amount *help	¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000) Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000) Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000) Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords	子宮内膜環境 / HIF-1 / 低酸素 / 炎症 / 着床 / EMT / 子宮内膜
Outline of Research at the Start	本研究の目的は、子宮内酸素環境、HIF-1、炎症の相互関係の解析と関係の存在の証明でありそれらが子宮内膜由来の上皮細胞、間質細胞の分化・機能に与える影響を検討することである。炎症性サイトカイン・物質、酸素環境などの子宮内環境が転写因子HIF-1活性化調節を通じて子宮内膜由来細胞(子宮内膜上皮、子宮内膜間質細胞)機能に与える影響の検討を行う。
Outline of Final Research Achievements	The partial pressure of oxygen in the endometrium is highly variable, thus mandating the investigation of the involvement of hypoxia-inducible factors (HIFs) in endometrial tissue. On the other hand, there are various phenomena that cannot be explained by the classical dogma that "HIF activation = hypoxia," and one of the key words is inflammation. The purpose of this study is to demonstrate the interrelationship between intrauterine oxygenation, HIF, and inflammation, and to analyze their effects on the differentiation and function of endometrial cells. Recently, the focus has been on the relationship between chronic endometritis and implantation disorders, and epithelial-mesenchymal transition(EMT) is thought to play an important role during implantation. In this study, we found that HIF and EMT-inducing factors were induced by inflammatory cytokines and hypoxia. This result suggests that HIF and EMT-inducing factors induced by chronic endometritis may affect implantation function.
Academic Significance and Societal Importance of the Research Achievements	慢性子宮内膜炎は不妊症の原因になると考えられている。細菌感染や種々の要因による反応性過程と考えられているが、画一された診断基準がなく、病態についても解明されていない点が多い。治療として抗菌薬やプロバイオティクスの投与が行われているが、明確な効果判定法もなく、その後の不妊治療成績への寄与も不明である。今回我々は子宮内酸素環境-HIF-1-炎症の相互関係に着目し、炎症性サイトカインおよび低酸素症に誘導されるHIFおよびEMT因子が着床機能に影響を与える可能性を示すことにより、慢性子宮内膜炎の病態解明につなげることができた。