Toll-like Receptors in the Intestinal Epithelium: Receptors of Survival or Death or Both?

肠上皮中的 Toll 样受体：生存或死亡或两者兼而有之的受体？

• 批准号: 5356696
• 负责人: Professorin Dr. Elke Cario
• 金额: --
• 依托单位: Klinik für Gastroenterologie und Hepatologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2002
• 资助国家: 德国
• 起止时间: 2001-12-31 至 2003-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5356696?language=en
• 关键词: Toll; like; Receptors; Intestinal; Epithelium

The intestinal epithelium serves as an essential defensive barrier of the mucosal immune system that forms a bipolar interface between the diverse populations of microbes of the lumen and subjacent immune cells present in the lamina propria. Intestinal epithelial cells (IEC) express Toll-like receptors (TLR) as pattern recognition receptors at their apical pole - poised to recognize microbial "pathogen-associated molecular patterns" (PAMPs) as "non-self" and to rapidly initiate innate immune responses. Lumenal PAMPs play a central role in initiation and perpetuation of inflammatory bowel disease (IBD). Recent studies have demonstrated that intestinal epithelial TLR expression is differentially altered in IBD. However, so far, very little is known, about the complex recognition mechanisms and functional immune consequences of TLRs through which the intestinal epithelium constantly interacts with PAMPs. Parallel activation of intestinal epithelial pro- and anti-apoptosis reflects an essential mechanism of mucosal immune defense which appears to be severely imbalanced in IBD. It remains elusive whether PAMP-induced activation of TLRs may mediate apoptosis in IEC. Thus, the aim of this research project is to characterize the potential checkpoint function of TLRs and interacting signaling cascades under physiological and pathophysiological conditions - distinctly triggering either pro- or anti-apoptosis in IEC in response to specific PAMPs in vitro and in vivo. Long-term goal is to comprehend the pathogenetic role of intestinal epithelial TLR dysregulation in IBD and to develop new therapeutic strategies of modulation of immune dysfunction.

肠上皮是粘膜免疫系统的基本防御性障碍，在层中存在于椎板上存在的腔内微生物和次要免疫细胞之间形成双极界面。肠上皮细胞（IEC）在其顶杆处表现为模式识别受体，表达了类似的受体 - 有望识别微生物“病原体相关的分子模式”（PAMPS）为“非自身”，并迅速引发先天免疫反应。 Lumenal PAMPS在炎症性肠病（IBD）的启动和延续中起着核心作用。最近的研究表明，肠上皮TLR表达在IBD中有差异改变。然而，到目前为止，关于TLR的复杂识别机制和功能免疫后果的知之甚少，肠上皮不断与助理相互作用。肠上皮和抗凋亡的平行激活反映了粘膜免疫防御的基本机制，在IBD中似乎严重失衡。是否难以捉摸地诱导的TLR激活可以介导IEC中的凋亡。因此，该研究项目的目的是在生理和病理生理条件下表征TLR的潜在检查点功能和相互作用的信号传导级联反应 - 响应特定的体外和体内响应特定的PAMP，从而明显触发IEC中IEC或抗凋亡。长期目标是理解IBD肠上皮TLR失调的致病作用，并制定免疫功能障碍调节的新治疗策略。