Flagellin-induced gut epithelial chemokine secretion

鞭毛蛋白诱导肠上皮趋化因子分泌

• 批准号: 6577688
• 负责人: Andrew T Gewirtz
• 金额: $ 24.32万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-15 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6577688
• 关键词: Salmonella typhimurium; arachidonate; biological signal transduction; biopsy; calcium flux; chemokine; clinical research; enzyme activity; flagellin; gastrointestinal epithelium; gene expression; host organism interaction; human subject; inflammatory bowel diseases; interleukin 8; intracellular transport; laboratory rabbit; microorganism immunology; mitogen activated protein kinase; neutrophil; protein protein interaction; secretion; toll like receptor

DESCRIPTION (provided by applicant): The active flares of colitis (collectively referred to as inflammatory bowel disease [IBD]) are characterized by migration of neutrophils to the intestinal lumen forming an intestinal crypt abscess. Such neutrophil movement is directed via polarized chemokine secretion by the epithelial cells that line the intestine. As I transitioned from trainee to faculty, I elucidated the mechanism by which such epithelial chemokine secretion is regulated. Briefly, I found that epithelial Ca++ mobilization is a key signal regulating such chemokine secretion. Further, such chemokine secretion is activated via the protein flagellin that is secreted by bacteria. Flagellin is secreted by commensal and pathogenic bacteria. However, only flagellin that crosses epithelia to the basolateral membrane domain activates epithelial chemokine secretion. Such translocation of flagellin is mediated by pathogens, but not commensal bacteria, explaining why, normally, only pathogenic bacteria induce epithelia to orchestrate inflammation. However, aberrant translocation of, and/or responses to, flagellin may occur in IBD and thus may underlie the inappropriate chemokine secretion that occurs in IBD. For my first independent award application, I propose to expand on the above studies while investigating the hypothesis that bacterial-epithelial interactions regulate the neutrophil infiltration (i.e., active inflammation) associated with both innate immunity and IBD. Consequently, pharmacologic manipulation of these interactions can be therapeutic for IBD. This hypothesis will be studied in vitro and in vivo via three specific aims, all of which are supported by substantial preliminary data. Specifically, I will characterize bacterial translocation of flagellin across intestinal epithelia, investigate how flagellin activates epithelial chemokine secretion, and further define the activation of anti-inflammatory signaling pathways by lipoxins. In vitro and in vivo models will be utilized.

描述（由申请人提供）：结肠炎的活动性发作（统称为炎症性肠病[IBD]）的特征是中性粒细胞迁移至肠腔形成肠隐窝脓肿。 这种中性粒细胞的运动是通过肠道上皮细胞分泌的极化趋化因子来引导的。 当我从实习生转变为教师时，我阐明了这种上皮趋化因子分泌的调节机制。 简而言之，我发现上皮 Ca++ 动员是调节此类趋化因子分泌的关键信号。 此外，这种趋化因子分泌是通过细菌分泌的蛋白质鞭毛蛋白激活的。 鞭毛蛋白由共生菌和病原菌分泌。 然而，只有穿过上皮到达基底外侧膜域的鞭毛蛋白才能激活上皮趋化因子的分泌。 鞭毛蛋白的这种易位是由病原体介导的，而不是由共生细菌介导的，这解释了为什么通常只有病原菌才会诱导上皮细胞来协调炎症。 然而，IBD 中可能发生鞭毛蛋白的异常易位和/或对鞭毛蛋白的反应，因此可能是 IBD 中发生的不适当趋化因子分泌的基础。 对于我的第一个独立奖项申请，我建议扩展上述研究，同时调查细菌-上皮相互作用调节与先天免疫和 IBD 相关的中性粒细胞浸润（即活动性炎症）的假设。 因此，对这些相互作用的药理学操作可以治疗 IBD。 该假设将通过三个具体目标在体外和体内进行研究，所有这些都得到大量初步数据的支持。 具体来说，我将描述鞭毛蛋白跨肠上皮的细菌易位，研究鞭毛蛋白如何激活上皮趋化因子分泌，并进一步定义脂氧素对抗炎信号通路的激活。将利用体外和体内模型。