Fas/FasL通过自噬调控门静脉高压性胃病的作用机制

Portal hypertensive gastropathy (PHG) is one of the main complications of the patients associated with liver cirrhosis. Our previous data has demonstrated mucosal apoptosis plays an important role in PHG, and we also revealed this apoptosis was depended on ER stress/PUMA-mediated mitochondrial apoptotic signaling. In our subsequent research indicated that β-arrestin1 involves in the downregulation of ER stress/PUMA-mediated apoptotic signaling, which could attenuate the mucosal injury of PHG. In our recent study, we also found that death receptor signaling family member FasL and its receptor Fas and autophagy participate in the mucosal apoptosis of PHG, but the definite mechanism has not been fully clarified and needed to be explored in our further research. Based on these above, the applying project intends to investigate whether and how Fas/FasL regulate the mucosal autophagy by using PHG patients' sections and mice PHG models in FasL knockout mice, and to analyze the definite mechanism of Fas/FasL-regulated mucosal autophagy in PHG, and to provide scientific basis for develop new therapeutic drugs.

门静脉高压性胃病（PHG）是肝硬化重要的并发症之一，我们以前的研究结果显示胃黏膜细胞凋亡在PHG中发挥着重要作用，进一步的研究发现这种凋亡是通过ER stress/PUMA诱导的线粒体依赖性的信号通路发生的，并且G蛋白偶联受体相关蛋白β-arrestin1能下调ER stress/PUMA诱导的凋亡而减轻PHG的黏膜损伤。最近，我们的前期工作又发现死亡信号FasL及其受体Fas和自噬在PHG胃黏膜凋亡中发挥着重要作用，但其具体机制不清楚。本项目拟在上述工作基础上，采用PHG临床样本、FasL基因缺失的小鼠PHG模型，分析Fas/FasL如何通过自噬调控PHG的发病，并阐明其机制。本项目有望揭示PHG新的分子机制，为相关治疗靶点提供科学依据。

门静脉高压性胃病是门静脉高压症的一种常见的并发症。有研究已证实血流动力学、肝脏的代谢功能、胃粘膜的保护屏障受损、TNF-α、VEGF、TGF-α/β、ET-1、iNOS、PGE2、VEGF及内毒素等与门静脉高压性胃病的胃粘膜损伤有关，但其确切的发病机制尚不清楚。我们以前研究显示上皮细胞的损伤与凋亡在门静脉高压性胃病中发挥着重要的作用(Cell Research. 2009, 19: 1269-1278)，后续研究中进一步证实了β-arrestin1、PGE2/EP4及ER Stress/PUMA相关通路参与调控门静脉高压性胃病胃粘膜的损伤与凋亡中(Cell death and disease. 2014, e1128；Free radical biology and medicine. 2015, 87: 69-83；British Journal of Pharmacology. 2017, 174: 848-866)。在本项基金的大力支持下，我们进行深入研究发现，Fas和其配体FasL、NF-κBp65以及自噬相关蛋白在人及小鼠门静脉高压性胃病胃粘膜组织中的表达明显上调。同时，IL-6及其受体IL-6R在门静脉高压性胃病胃粘膜组织中表达亦明显增加，特异性的IL-6/IL-6R抑制剂能明显下调Fas/FasL及门静脉高压性胃病胃粘膜的损伤与凋亡。最后采用基因型小鼠及原代细胞证实，在门静脉高压性胃病发病过程中，Fas/FasL可通过调控NF-κBp65、自噬通路来介导门静脉高压性胃病的胃粘膜上皮细胞损伤及凋亡（Cell Death and Disease. 2019, 10: 748）。上述研究有望将Fas/FasL调控的相关通路确定为门静脉高压性胃病新的治疗靶点提供了坚实的科学理论依据，这对于寻找门静脉高压性胃病新的药物治疗靶点，达到有效防治门静脉高压性胃病的目的，具有非常重要的科学意义。