Ferroptosis在门脉高压性胃病中的作用及NF-κBp65/BECN1对其调控的机制

我们在前二个国家自然基金面上项目资助下，证实了凋亡是门脉高压性胃病（PHG）重要的病理特征，揭示了关键调控机制，发表了一系列成体系的研究论文，均已圆满结题。在最近的研究中，我们又发现另一种新的细胞死亡形式Ferroptosis在PHG中起着重要作用。我们前期对临床样本及小鼠模型研究，发现Ferroptosis相关铁蛋白FTH和FTL在PHG黏膜中显著升高，并与细胞死亡及线粒体损伤呈正相关，但机制不清楚，有待进一步研究。本项目拟在前期工作基础上，采用门脉高压动物模型，研究Ferroptosis在PHG中的作用，在基因缺失小鼠上研究β-arrestin1是否通过NF-κBp65/BECN1介导自噬来调控胃黏膜的Ferroptosis，并分析其调控机制。最后采取PHG患者的胃黏膜样本来验证这种作用。本项目将揭示Ferroptosis在PHG中的作用及其分子机制，为新的靶点药物开发提供科学依据。

In two completed NSFC fund support, we have confirmed that gastric mucosal apoptosis is a prominent pathological feature in portal hypertensive gastropathy (PHG), revealed its molecular mechanism, and published a series of research articles including Cell Res, Cell Death Dis, Free Radic Biol Med, Br J Pharmacol, etc. In further study, we found that another new cell death different from Apoptosis, Ferroptosis, plays a very important role in PHG. Our data showed that ferroptosis-associated ferritin (FTH and FTL) were significantly elevated in PHG, and correlated with cell death and mitochondrial damage. However, the effect of ferroptosis and its mechanism are unclear. Base on the above study, the applying project intends to use portal hypertension animal models to investigate the pathological role of ferroptosis, to study whether β-arrestin1 regulates the gastric mucosal ferroptosis via NF-κBp65/BECN1-mediated autophagy using β-arrestin1 and NF-κBp65 deficient mice, and to analyze its molecular mechanism. Finally, the gastric mucosal samples from PHG patients were used to verify this effect. This project is expected to reveal the effect of ferroptosis on PHG and its molecular mechanism, find new therapeutic targets, and provide scientific basis for the development of related new drugs.