MTDH靶向PKM2调控β-catenin活化入核介导糖尿病肾病足细胞损伤的机制研究

批准号:
82000682
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
陈晓雯
依托单位:
学科分类:
继发性肾脏疾病
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
陈晓雯
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中文摘要
足细胞损伤是糖尿病肾病(DKD)发生发展的关键因素,但其具体机制未明。我们前期发现异粘蛋白MTDH高表达于DKD足细胞并活化β-catenin通路促进足细胞损伤,质谱分析筛选出与MTDH有效结合的蛋白丙酮酸激酶M2(PKM2)并发现MTDH可通过调控PKM2酶活性及其单体功能诱导β-catenin活化入核。据此我们提出:MTDH通过解聚PKM2抑制其酶活性导致线粒体损伤,激活β-catenin;同时MTDH结合PKM2单体携带β-catenin促进β-catenin入核活化下游靶基因的表达,诱导足细胞损伤。本项目拟通过构建足细胞特异性MTDH基因敲除小鼠并采用超声微泡基因转导、免疫共沉淀、双荧光素酶报告系统等技术,以MTDH调控PKM2/β-catenin为切入点,从体内外探索MTDH介导DKD足细胞损伤的分子机制。本项目对阐明DKD的致病机制、寻找潜在治疗靶点具有重要意义。
英文摘要
Podocyte injury is a critical factor for the development of diabetic kidney disease (DKD). However, the potential mechanism remains poorly understand. Previously, we found that metadherin (MTDH) was increased in podocytes of DKD and promoted podocyte injury through activating β-catenin signaling. Using mass spectrometry analysis, we screened out pyruvate kinase M2 (PKM2) that could effectively bind with MTDH. Additionally, we found that MTDH might induce β-catenin activation and its nuclear translocation through modulating the enzyme activity of PKM2 and its monomer function. Based on our previous studies, we hypothesize that MTDH inhibits the enzyme activity of PKM2 through depolymerizing PKM2 and then induces mitochondrial damage leading to β-catenin activation; at the same time, MTDH binds to PKM2 monomer and then carry β-catenin,which will promote nuclear translocation of β-catenin to transcribe the target genes, thereby inducing podocyte injury. In this study, we will take the regulation of PKM2/β-catenin by MTDH as a breakthrough point and explore the molecular mechanism by which MTDH mediates podocyte injury in DKD in vitro and in vivo by using podocyte-specific MTDH knockout mice, ultrasound microbubbles mediated gene transduction, co-immunoprecipitation and dual luciferase report system. This study is of great significance for elucidating the pathogenic mechanism of DKD and looking for the potential therapeutic targets for DKD.
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DOI:10.1186/s12967-023-04469-w
发表时间:2023-09-19
期刊:JOURNAL OF TRANSLATIONAL MEDICINE
影响因子:7.4
作者:Li, Shuting;Luo, Congwei;Chen, Sijia;Zhuang, Yiyi;Ji, Yue;Zeng, Yiqun;Zeng, Yao;He, Xiaoyang;Xiao, Jing;Wang, Huizhen;Chen, Xiaowen;Long, Haibo;Peng, Fenfen
通讯作者:Peng, Fenfen
DOI:DOI: 10.1016/j.trsl.2023.11.006
发表时间:2023
期刊:Translational Research
影响因子:7.8
作者:Xiaowen Chen;Jing Xiao;Danping Tao;Yunyi Liang;Sijia Chen;Lingyu Shen;Shuting Li;Zerong Zheng;Yao Zeng;Congwei Luo;Fenfen Peng;Haibo Long
通讯作者:Haibo Long
MTDH-PGAM1轴调控糖酵解介导FOXO3a乳酸化修饰促进糖尿病肾病肾小管上皮细胞损伤的机制研究
- 批准号:--
- 项目类别:省市级项目
- 资助金额:30.0万元
- 批准年份:2024
- 负责人:陈晓雯
- 依托单位:
国内基金
海外基金
