Intestinal Epithelial Tight Junction Structure-Function

描述(申请人提供)：炎症性肠病的特征是肠道炎症、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连接的调节，这些连接包括紧密连接(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。粘膜炎症扰乱了细胞间连接和上皮的动态平衡特性，从而导致上皮屏障的破坏。然而，我们对肠道炎症中细胞间连接蛋白串扰、上皮内稳态和受损上皮屏障的分子基础的了解非常有限。因此，这项建议的总体目标是确定细胞间连接蛋白控制上皮细胞内稳态和屏障功能的机制，并确定炎症对上皮屏障破坏的影响。我们将专门研究DM钙粘附素和TJ Claudin蛋白在调节肠上皮屏障中的作用。促炎细胞因子、IFNG和TNFa对这种调节过程的影响将被确定。除了深入了解肠上皮屏障调节的分子基础外，这些研究还将为开发促进肠上皮屏障功能和减轻粘膜炎症的治疗剂提供新的思路。这些研究还将为治疗药物/疫苗输送和癌症治疗提供瞬时干扰上皮屏障的策略。

DESCRIPTION (provided by applicant): 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- inflammatory cytokines, IFNg and TNFa 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 promote 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.