Vitamin D/VDR通过HIF-1α调控肠上皮细胞炎症反应在炎症性肠病中发挥作用

Inflammatory bowel disease (IBD) is a major inflammatory disorder in the gastrointestinal tract in humans. One principal pathological issue is that dysfunctional mucosal epithelial barrier leads to increased permeability and invasion of luminal bacteria, toxins and antigens, which trigger inflammatory response in the colon. Our previous studies have demonstrated that Vitamin D/VDR plays a key role in maintaining the integrity of colonic epithelial barrier to prevent IBD. Although numerous studies have confirmed Vitamin D/VDR can protect against IBD, the mechanism of this regulation in colonic epithelial cells remains incompletely understood. Some studies have reported that hypoxia induced factor-1α (HIF-1α) is involved in the development of IBD via mediating various inflammation-related genes, thus this time we will focus on the function of Vitamin D/VDR on colonic mucosal inflammation by regulating HIF-1α in colonic epithelial cells. Using in vitro cell cultures and in vivo experimental models, in this study we will explore the regulatory effect of Vitamin D/VDR on HIF-1α in colonic epithelial cells, and elucidate the mechanism whereby Vitamin D/VDR regulates HIF-1α signaling pathway in IBD by various molecular biological methods such as western blot、qPCR and ChIP assays. Furthermore, we will test the hypothesis that vitamin D suppresses colonic epithelial inflammation by regulating HIF-1α pathway, in order to provide novel methods for the prevention and management of IBD.

炎症性肠病（IBD）是一种特殊的肠道炎症性疾病,特征是肠黏膜屏障破坏后肠腔内有害物质激活机体免疫系统而引发的炎症反应。申请人前期工作证明维生素D及其受体 (Vitamin D/VDR)可以保护肠上皮细胞屏障并抑制IBD发生，但其调控肠黏膜炎症反应的具体分子机制尚不明晰。研究发现低氧诱导因子1α（HIF-1α）通过调控多种炎症相关基因参与IBD发生，因此这次我们将关注Vitamin D/VDR调控肠上皮细胞HIF-1α对肠黏膜炎症反应的影响。本项目以体外细胞和体内动物模型为研究对象，探究Vitamin D/VDR对肠上皮细胞HIF-1α的调控作用，结合western blot、qPCR、ChIP等多项分子生物学技术阐明这一调控作用的分子机制，并进一步验证Vitamin D/VDR通过HIF-1α通路调节肠上皮细胞炎症反应的假设，以期为预防和治疗炎症性肠病提供新的方法和思路。

研究报道维生素D及其受体VDR在炎症性肠病发生发展过程中发挥重要保护作用，且低氧诱导因子1α（HIF-1α）与化学药物诱导的小鼠炎症性肠病密切相关。但是在该疾病中，维生素D及其受体VDR与HIF-1α的相互调控作用尚不清楚。本项研究中，我们报道了炎症性肠病患者病变部位结肠上皮细胞HIF-1α高表达，体外结肠上皮细胞实验证实肿瘤坏死因子TNFa通过NF-kB信号通路激活HIF-1α。在野生型C57BL/6动物模型中，HIF-1α抑制剂预处理明显改善TNBS或DSS诱导的小鼠炎症性肠病症状。此外，无论是体外细胞模型还是体内动物模型，维生素D及其受体VDR都通过抑制NF-kB信号通路活性降低结肠上皮细胞HIF-1α高表达，进而降低结肠上皮细胞IFNr和IL-1b炎性因子的生成。总之，我们的研究成果证明维生素D及其受体VDR可以通过抑制结肠上皮细胞HIF-1α高表达改善小鼠炎症性肠病症状。这一发现为临床应用维生素D治疗IBD提供了新思路。项目资助发表了SCI论文3篇，联合培养了博士研究生1名，目前在读。项目投入经费21万元，支出21万元，各项支出基本与预算相符。