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

体内平衡和炎症过程中连接粘附分子 A (JAM-A) 对肠道屏障的调节

• 批准号: 455209265
• 负责人: Dr. Kevin Börner
• 金额: --
• 依托单位: Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I)
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/455209265?language=en
• 关键词: Regulation; intestinal; barrier; Junctional; Adhesion

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.

肠上皮屏障(IEB)在保护肠腔抗原的同时，允许营养物质的细胞旁运输和吸收，起着至关重要的作用。肠粘膜损伤导致局部免疫反应加剧，进而导致炎症、组织损伤和屏障破坏，所有这些都与慢性炎症性胃肠道疾病相关，如炎症性肠病(IBD)。因此，有效的粘膜修复是重建屏障和维持肠道功能的关键。研究发现紧密连接蛋白Jam-A(JAM-A)是一种调节肠道内环境平衡的蛋白。JAM-A的缺失已被证明可以增加肠道通透性，减少中性粒细胞向肠道的募集，并损害肠上皮细胞的迁移。尽管它明显参与了肠道内环境的稳定--这一状态在IBD中受到了极大的干扰--但关于JAM-A在上皮伤口愈合中的作用尚不清楚。在这个项目中，我们将研究上皮性JAM-A是如何调节肠粘膜伤口修复和动态平衡的。为此，将使用模型肠上皮细胞系(SK-CO15，T84)、原代小鼠上皮细胞(结肠癌)和具有完全敲除或可诱导的上皮特异性JAM-A丢失的小鼠品系进行补充的体外和体内工作。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在粘膜修复中的作用。这项建议的初步工作表明，肠道上皮细胞中JAM-A缺乏会损害体内伤口的闭合。了解上皮性JAM-A调节黏膜伤口愈合和肠道屏障特性的机制将为了解IBD等慢性肠炎的病理生理提供重要的见解。