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。上皮屏障功能受一系列细胞间蛋白的调节 包括紧密连接(TJ)、粘着连接(AJ)和桥粒(DM)的连接。现在是时候了 显然，细胞间连接是高度动态的结构，其组成蛋白是活跃的 参与调节上皮细胞动态平衡。粘膜炎症扰乱细胞间连接和 上皮细胞的动态平衡特性，从而导致上皮屏障受损。我们对这一点的了解 细胞间连接蛋白串扰、上皮细胞动态平衡和受损上皮细胞的分子基础 然而，肠道炎症的屏障非常有限。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和屏障功能的机制 确定炎症对上皮屏障破坏的影响。我们将具体审查这一角色 糖尿病钙粘附素和TJ Claudin蛋白在调节肠上皮屏障中的作用。亲和派的影响 这种调控过程中的抗炎细胞因子将被确定。除了获得洞察力之外 深入探讨肠上皮屏障调节的分子基础，这些研究将为肠道上皮屏障的研究提供新思路 增强肠上皮屏障功能和减少粘膜损伤的治疗剂的研究进展 发炎。这些研究还将提供对暂时性扰乱上皮细胞的策略的洞察 治疗药物/疫苗输送和癌症治疗的障碍。

Abstract Inflammatory bowel diseases are characterized by intestinal inflammation, increased mucosal cytokines and compromised epithelial barrier function. Epithelial barrier function is regulated by a series of 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 perturbs intercellular junctions and epithelial homeostatic properties thereby resulting in epithelial barrier compromise. Our knowledge of the molecular basis of intercellular junction protein cross-talk, epithelial homeostasis and compromised epithelial 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 and barrier function and determine the influence of inflammation on epithelial barrier compromise. We will specifically examine the role of DM cadherins and TJ claudin proteins in regulating the intestinal epithelial barrier. The influence of pro- and anti-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 function and reduce mucosal inflammation. These studies will also provide insight into strategies of transiently perturbing the epithelial barrier for therapeutic drug/vaccine delivery and cancer therapy.