The role of LOX-1 in inflammatory activation of microglial under hypoxic-ischemic conditions

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16875
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: University of Miyazaki (2021-2022); Tokyo Metropolitan Children's Medical Center (Department of Clinical Research) (2020)
• Principal Investigator: Aoki Yoshinori 宮崎大学, 医学部, 助教 (70726629)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 新生児低酸素性虚血性脳症

Outline of Final Research Achievements

I performed oxygen glucose deprivation treatment of primary rat microglial cells and evaluated the expression levels of LOX-1, cytokines and chemokines using siRNA and inhibitors. As a result, I found that defects in oxygen and nutrition induced LOX-1 expression and led to the production of inflammatory mediators, such as the cytokines and the chemokines. Then, the LOX-1 signal transduction pathway was blocked by inhibitors, LOX-1 siRNA, the p38-MAPK inhibitor SB203580, and the NF-κB inhibitor BAY11-7082, and the production of inflammatory mediators was suppressed. Moreover, it was hypothesized that LOX-1 in microglial cells was autonomously overexpressed by positive feedback of the intracellular LOX-1 pathway. Microglial cells are known to contribute to various neurological diseases. Hypoxic and ischemic brain injuries result in lifelong neurological and mental deficiency. LOX-1 and its related molecules or chemicals may be major therapeutic candidates.

Free Research Field

小児科学

Academic Significance and Societal Importance of the Research Achievements

新生児低酸素性虚血性脳症は先進国において1000出生あたり1-8の発生率であり、重篤な後遺症につながる予後不良な疾患である。低体温療法などすでに臨床に導入されている治療法があるものの、いまだに治療効果としては不十分であり、有効な治療法の開発が望まれている。
本研究成果からv、LOX-1とそのシグナル伝達経路は新生児低酸素性虚血性脳症に対する新しい治療法開発のターゲットとなることが再確認された。さらに、本研究の細胞モデルは今後の新規治療法開発に役立つものであり、本研究ではそのような有用な実験系の確立、および新規治療法開発につながる重要な知見を発見することができた。