Elucidation of the role of Txnip in the pathogenesis of sepsis-induced hyperglycemia and its therapeutic application

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08951
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55050:Anesthesiology-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Ishii Sachiyo 京都府立医科大学, 医学(系)研究科(研究院), 講師 (40457958)
• Co-Investigator(Kenkyū-buntansha): 飯田 淳 京都府立医科大学, 医学(系)研究科(研究院), 助教 (20515283)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 敗血症 / 高血糖

Outline of Final Research Achievements

We believe that promotion of inflammatory responses and cellular dysfunction triggered by increased expression of Txnip are involved in the worsening of the disease condition in sepsis-induced hyperglycemia, and that inhibiting the binding of Txnip to GLUT1 will improve the disease condition. So static and molecular dynamics analysis of protein-protein interaction between Txnip and GLUT1 receptor was performed.
We assumed that multiple bases common to both static and dynamic analyzes were bases related to protein-protein interactions, and created multiple combinations of alanine substitution mutants to narrow down the bases. We are currently conducting experiments to determine which Txnip mutant abolishes GLUT1 receptor endocytosis.

Free Research Field

麻酔

Academic Significance and Societal Importance of the Research Achievements

敗血症は免疫機能低下と高血糖症を引き起こし、続発する高血糖症は敗血症の病態を悪化させるが、このメカニズムとして我々はTxnipの発現上昇をトリガーとした炎症応答促進や細胞機能不全が関与していると考えている。今回Txnipの発現上昇により酸化ストレスや小胞体ストレスが引き起こされていることや、TxnipがHSP70とタンパク質相互作用する可能性が判明し、シャペロンの直接阻害による小胞体ストレス誘導経路の可能性も示唆された。これらのTxnipの作用をさらに明らかにすることで高血糖症による敗血症の病態悪化を食い止める治療法につながる可能性がある。