Clarification of new oxidative signaling involved in tissue fibrogenesis and its application to therapeutic strategy

Research Project

Project/Area Number	16K08552
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	General pharmacology
Research Institution	Kyoto Prefectural University of Medicine
Principal Investigator	Katsuyama Masato 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (60315934)
Research Collaborator	IWATA Kazumi YABE Chihiro (NISHIMURA Chihiro)
Project Period (FY)	2016-04-01 – 2019-03-31
Project Status	Completed (Fiscal Year 2018)
Budget Amount *help	¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000) Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000) Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000) Fiscal Year 2016: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywords	活性酸素 / 組織線維化 / NADPHオキシダーゼ / 薬理学 / 活性酸素種
Outline of Final Research Achievements	It is well known that NOX4/NADPH oxidase is involved in fibrogenesis. In human lung fibroblasts transfected with siRNAs against NOX4, levels of endoglin, a co-receptor of TGF-β, were reproducibly decreased at protein levels compared with those in control siRNA-transfected cells. Results from experiments using pharmacological inhibitors suggested that NOX4-derived reactive oxygen species (ROS) stabilize endoglin and maintain its functional expression at cell membranes by regulating atypical PKC. On the other hand, NOX4A mRNA is a splice variant of NOX4 mRNA with only 4-base deletion in the coding region. Exogenous expression of NOX4A suggested that it is a small protein corresponding to the N-terminus of NOX4 and generates ROS.
Academic Significance and Societal Importance of the Research Achievements	組織線維化は不可逆的な変化であり、根治可能な薬物療法は現在のところ存在しない。NOX4は活性酸素種（ROS）を産生するNADPHオキシダーゼの触媒サブユニットの一分子種であり、NOX4が産生するROSは組織線維化に重要な役割を果たすが、その分子機構は未解明の点が多い。本研究では、NOX4由来ROSがTGF-βのシグナリングを増強するメカニズムの一端を示唆する結果を得ることができた。またNOX4によるROS産生の一部がスプライスバリアントを介するものである可能性を明らかにした。本研究成果は新たな抗線維化薬の開発のための基礎的知見となるものと考えている。