源于活化Kupffer细胞内的miR-199a-5p负调控Brg1/Nrf2通路在移植肝缺血再灌注损伤中的作用

The mechanism of Kupffer cell activation involved in the hepatic ischemia reperfusion injury has not been elucidated. Using miRNA chip, we firstly found that miR-199a-5p from Kupffer cells in liver transplantation increased significantly. It can reduce the damage of co cultured hepatocytes, when miR-199a-5p is antagonistic, which might be an important cause of liver graft damage deterioration. The related research showed that miRNA via gap junctions (direct contact) or exosomes (non direct contact) transfered between cells, bring obvious damage effects. Our previous studies indicated that GJ delivered nociceptive information and Brg1 regulated the transcription of antioxidant enzymes mediated by Nrf2. Using Targetscan and Pictar software analysis, we predicted one of the downstream target genes of miR-199a-5p is just Brg1. Accordingly, it is suggested that the negative regulation of Brg1/Nrf2 pathway mediated by miR-199a-5p from the activated Kupffer cells involved in the liver graft injury. This project is carried out on the basis of our previous studies, and focuses on the miR-199a-5p itself and its signal transduction pathway. Thus, the genetically engineered mice, plasmid transfection or silence, inhibitors and agonists were used to clarify the mechanism of liver graft injury mediated by Kupffer cell, providing a new target and theoretical basis for the prevention and treatment of liver graft injury.

Kupffer细胞活化参与移植肝缺血再灌注损伤的发生及恶化机制仍未阐明。我们用miRNA芯片发现源于移植肝组织Kupffer细胞中miR-199a-5p含量显著升高，拮抗它使共培养肝细胞损伤减轻；相关研究提示miRNA能经缝隙连接（GJ）或外泌体在细胞间传递。我们已经证明GJ传递了伤害性信息；Brg1调控Nrf2介导的抗氧化酶转录，同时用生物信息学预测及预实验显示miR-199a-5p下游靶基因可能为Brg1。据此设想：源于活化Kupffer细胞的miR-199a-5p负调控Brg1/Nrf2通路参与移植肝损伤，是移植肝损伤发生和恶化关健所在。本项目是在前期基础上开展的延续研究，拟对miR-199a-5p本身及其传递途径进行干预，采用了基因工程小鼠、质粒转染或沉默、相关抑制剂和激动剂等工具，阐明Kupffer细胞引起移植肝损伤的关健作用及调控机制，为寻找移植肝损伤保护治疗靶点提供科学依据。

Kupffer细胞活化参与移植肝缺血再灌注损伤的发生及恶化机制仍未阐明。我们用miRNA芯片发现源于移植肝组织Kupffer细胞中miR-199a-5p含量显著升高，拮抗它使共培养肝细胞损伤减轻；相关研究提示miRNA能经缝隙连接（GJ）或外泌体在细胞间传递。我们已经证明GJ传递了伤害性信息；Brg1调控Nrf2介导的抗氧化酶转录，同时用生物信息学预测及预实验显示miR-199a-5p下游靶基因可能为Brg1。本项目是在前期基础上开展的延续研究，对miR-199a-5p本身及其传递途径进行干预，采用了基因工程小鼠、质粒转染或沉默、相关抑制剂和激动剂等工具，阐明了Kupffer细胞引起移植肝损伤的关健作用及调控机制，证实了源于活化Kupffer细胞的miR-199a-5p负调控Brg1/Nrf2通路参与移植肝损伤，是移植肝损伤发生和恶化关健所在，为寻找移植肝损伤保护治疗靶点提供科学依据。

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