Regulation of intestinal barrier by Junctional Adhesion Molecule-A (JAM-A) during homeostasis and inflammation

肠上皮屏障（IEB）在保护肠腔抗原，同时允许营养物质的细胞旁转运和吸收方面起着至关重要的作用。肠粘膜损伤导致局部免疫应答加剧，进而导致炎症、组织损伤和屏障破坏，所有这些都是与慢性炎性胃肠道病变如炎性肠病（IBD）相关的病症。因此，有效的粘膜修复对于重建屏障和维持肠道功能至关重要。研究已经确定紧密连接蛋白连接粘附分子-A（JAM-A）作为肠内稳态的调节剂。已经证明JAM-A的缺失增加肠通透性，减少中性粒细胞向肠道的募集并损害肠上皮细胞迁移。尽管其明确参与肠道内稳态-IBD中的一种极大扰动的状态-但对JAM-A在上皮伤口愈合中的作用一无所知。在这个项目中，我们将研究上皮细胞JAM-A如何调节肠粘膜创伤修复和稳态。为此，将使用模型肠上皮细胞系（SK-CO 15、T84）、原代鼠上皮细胞（类结肠）和具有完全敲除或诱导型上皮特异性JAM-A缺失的小鼠品系进行补充性体外和体内研究。将分析伤口闭合、中性粒细胞募集和上皮迁移，以进一步表征上皮JAM-A在粘膜修复中的功能。该提案的初步工作表明，肠上皮细胞中的JAM-A缺陷会损害体内伤口闭合。了解上皮JAM-A调节粘膜伤口愈合和肠屏障特性的机制将为慢性肠道炎症性疾病（如IBD）的病理生理学提供重要见解。

The intestinal epithelial barrier (IEB) plays a vital role in protecting from luminal antigens while allowing for paracellular transport and absorption of nutrients. Intestinal mucosal injury leads to an exacerbated local immune response, which in turn results in inflammation, tissue damage and barrier breakdown, all of which are conditions associated with chronic inflammatory gastrointestinal pathologies such as inflammatory bowel disease (IBD). Efficient mucosal repair is thus critical to re-establish barrier and uphold intestinal function. Studies have identified the tight junction protein Junctional Adhesion Molecule-A (JAM-A) as a regulator of intestinal homeostasis. Loss of JAM-A has been demonstrated to increase intestinal permeability, decrease neutrophil recruitment to the gut and impair intestinal epithelial cell migration. Despite its clear involvement in intestinal homeostasis - a state greatly perturbed in IBD - nothing is known about the role of JAM-A in epithelial wound healing. In this project we will investigate how epithelial JAM-A regulates intestinal mucosal wound repair and homeostasis. For this, complementary in vitro and in vivo work will be conducted using model intestinal epithelial cell lines (SK-CO15, T84), primary murine epithelial cells (colonoids), and mouse strains with a total knockout or inducible, epithelial-specific loss of JAM-A. Wound closure, neutrophil recruitment and epithelial migration will be analyzed to further characterize the function of epithelial JAM-A in mucosal repair. Preliminary work for this proposal suggests that JAM-A deficiency in intestinal epithelial cells impairs wound closure in vivo. Understanding the mechanisms by which epithelial JAM-A modulates mucosal wound healing and intestinal barrier properties will provide important insights into the pathophysiology of chronic intestinal inflammatory conditions such as IBD.