Regulation of intestinal epithelial barrier function by intercellular junction proteins in health and disease

摘要 炎症性肠病的特征在于肠道炎症、粘膜细胞因子增加和炎症性细胞因子缺乏。 上皮屏障功能受损上皮屏障功能由细胞间连接调节， 包括紧密连接（TJ）、粘附连接（AJ）和桥粒（DM）。现在很明显， 细胞间连接是高度动态的结构，其组成蛋白积极参与 调节上皮细胞的稳态粘液性炎症损害上皮细胞的稳态特性 从而导致上皮屏障受损，这有助于疾病的发病机理。我们的知识 细胞间连接蛋白的相互作用、上皮细胞的稳态和屏障受损的分子基础 在肠道炎症中的作用非常有限。因此，本提案的总体目标是确定 细胞间连接蛋白控制上皮稳态、屏障功能和修复的机制 疾病受伤后。我们将专门研究两个关键的细胞间连接蛋白的作用， claudin 23和桥粒芯糖蛋白2在调节肠上皮屏障功能和损伤后修复中的作用。的 将确定炎性细胞因子对这种调节过程的影响。除了获得 深入了解肠上皮屏障调节的分子基础，这些研究将提供新的思路 用于开发增强肠上皮屏障、促进伤口修复 并减少粘膜炎症。这些研究也将提供洞察战略的瞬时 干扰上皮屏障以递送治疗药物/疫苗。

Abstract Inflammatory bowel diseases are characterized by intestinal inflammation, increased mucosal cytokines and compromised epithelial barrier function. Epithelial barrier function is regulated by intercellular junctions that encompass the tight junction (TJ), adherens junction (AJ) and desmosomes (DMs). It is now evident that intercellular junctions are highly dynamic structures and their component proteins actively participate in regulating epithelial homeostasis. Mucosal inflammation compromises epithelial homeostatic properties thereby resulting in epithelial barrier compromise which contributes to disease pathogenesis. Our knowledge of the molecular basis of intercellular junction protein cross-talk, epithelial homeostasis and compromised barrier in intestinal inflammation is however very limited. Thus the overall goals of this proposal are to identify mechanisms by which intercellular junction proteins control epithelial homeostasis, barrier function and repair after injury in disease. We will specifically investigate the role of two key intercellular junction proteins, claudin23 and desmoglein 2 in regulating the intestinal epithelial barrier function and repair after injury. The influence of inflammatory cytokines on such regulatory processes will be determined. In addition to gaining insights into the molecular basis of intestinal epithelial barrier regulation, these studies will provide new ideas for the development of therapeutic agents that strengthen the intestinal epithelial barrier, promote wound repair and reduce mucosal inflammation. These studies will also provide insight into strategies of transiently perturbing the epithelial barrier for therapeutic drug/vaccine delivery.