Molecular mechanism of neurodegeneration caused by modest static pressure

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07857
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Kindai University
• Principal Investigator: Yoneshige Azusa 近畿大学, 医学部, 助教 (70586750)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 機械的圧力 / 神経変性 / グリオーシス / 細胞死 / 鉄イオン

Outline of Final Research Achievements

Elevation of intraocular pressure is a major risk factor for glaucoma development, which causes the loss of retinal ganglion cells (RGCs). Lipocalin 2 (Lcn2) is upregulated in glaucomatous retinae; however, whether Lcn2 is directly involved in glaucoma is debated. In this study, retinal explant cultures were subjected to increased water pressure using a two-chamber culture device, and Lcn2 protein levels were examined by immunoblotting. In situ TUNEL and GFAP immunohistochemical assays were performed to assess apoptosis and gliosis, respectively. The Lcn2 protein levels, percentage of TUNEL-positive cells, and GFAP-positive area were significantly higher in retinae cultured under 50 cm H2O pressure loads compared to those cultured under 20 cm H2O. The negative effects of increased hydrostatic pressure were attenuated by the iron chelator deferoxamine. Modulating Lcn2 and iron levels may be a promising therapeutic approach for retinal degeneration.

Free Research Field

実験病理学

Academic Significance and Societal Importance of the Research Achievements

筆者らが開発した水柱下培養装置は生体内を模倣する実験モデルであり、内圧上昇とLcn2発現上昇、網膜神経節細胞層の神経変性との直接的な因果関係を証明した点が重要である。今後は網膜における内圧上昇の感作とLcn2をはじめとする神経変性因子発現誘導に至る分子機構の解明が必要で、特に内圧上昇感作におけるグリア細胞の役割が非常に興味深い。また、本研究において鉄イオンキレート剤であるDFOが網膜神経保護効果を示したことも、緑内障の新規治療法開発という観点において重要である。今後はLcn2発現上昇と組織内鉄イオン濃度の変化、それらによる細胞傷害機構の解明などを通して新規治療法開発につなげていきたい。