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

摘要 炎症性肠病的特点是肠道炎症，粘膜细胞因子增加和 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)、粘着连接(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 调节上皮细胞的动态平衡。粘膜炎症损害上皮内环境平衡特性 从而导致上皮屏障受损，从而参与疾病的发病机制。我们所了解的 细胞间连接蛋白串扰、上皮细胞动态平衡和屏障受损的分子基础 然而，对肠道炎症的影响非常有限。因此，这项提案的总体目标是确定 细胞间连接蛋白控制上皮内稳态、屏障功能和修复的机制 在疾病中受伤后。我们将专门研究两个关键的细胞间连接蛋白的作用， Claudin23和Desmoglein 2在调节肠上皮屏障功能和损伤后修复中的作用。这个 炎性细胞因子对这种调节过程的影响将被确定。除了获得 洞察肠上皮屏障调节的分子基础，这些研究将提供新的思路 用于开发增强肠道上皮屏障、促进伤口修复的治疗剂 并减轻粘膜炎症。这些研究还将提供对瞬息万变策略的洞察 扰乱治疗药物/疫苗输送的上皮屏障。

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.