THE ROLE OF BACTERIAL PEPTIDES IN CHRONIC INTESTINAL INFLAMMATION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 尽管经过了几十年的研究，但炎症性肠病(IBD)的基本致病机制仍不清楚。目前有许多疗法可用，但仍没有治愈克隆氏病和溃疡性结肠炎的方法，这些疾病的主要症状包括腹痛、溃疡、出血、体重减轻和腹泻。临床观察表明，肠道细菌可能触发并可能加剧炎症反应。然而，IBD的发病机制更有可能与任何特定的病原体本身无关，而与细菌产物有关，其中一些已在患者的肠道中检测到。 这一建议的中心假设是细菌肽，如N-甲酰-甲硫基-亮氨酰-苯丙氨酸(FMLP)，可能通过增加促炎细胞因子的基因表达，以及通过降低组织活力和改变运动能力来影响慢性结肠炎复发阶段的炎症反应。在患者的肠道中发现了FMLP，有证据表明该分子的上皮转运蛋白在炎症中异常表达。最近的发现表明，IBD的免疫反应是针对正常细菌菌群的，但对促炎和抗炎细胞因子之间发生的复杂相互作用知之甚少。中心假设将被系统检验如下：1.将研究fMLP在慢性再激活结肠炎模型中的作用及其本身引起再激活的能力(假设：在该模型中，fMLP可以启动炎症复发，并在复发性结肠炎的发病机制中起作用。)2.测定慢性复发性结肠炎患者应用fMLP后各种细胞因子的水平(假设：如果fMLP增加了损伤，则会观察到促炎细胞因子的增加，或免疫系统平衡的改变)。3.将评估fMLP在慢性复活性结肠炎肠道分泌反应和运动变化中的作用(假设：在动物复活性结肠炎模型中，通过给予fMLP引起的细胞因子水平的变化和神经调节剂的释放，可能改变结肠的离子运输过程和收缩反应，从而导致在人类情况下观察到的腹泻。) 了解慢性结肠炎中细菌肽诱导的免疫调节通路将为未来潜在的治疗干预提供新的途径，并将解决关于抗生素治疗有效性的争议。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Despite decades of research, the basic pathogenic mechanisms involved in inflammatory bowel disease (IBD) are still unknown. Many therapies are currently available, but there are still no cures for Crohn¿s disease and ulcerative colitis whose major symptoms include abdominal pain, ulceration, bleeding, weight loss, and diarrhea. Clinical observations have suggested that intestinal bacteria might trigger, and perhaps exacerbate, the inflammatory response. It is more likely, however, that the pathogenesis of IBD is not associated with any specific pathogen per se, but with bacterial products, some of which have been detected in the gut of patients. The central hypothesis of this proposal is that bacterial peptides such as N-formyl-methionyl-leucyl-phenylalanine (fMLP) may influence the inflammatory response in the relapse phase of chronic colitis through an increase in gene expression of pro- inflammatory cytokines, and through a decrease in tissue viability and alteration of motility. FMLP has been found in the intestine of patients, and there is evidence that epithelial transporters for this molecule are abnormally expressed in inflammation. Recent discoveries suggest that a dysregulated immune response is directed against the normal bacterial flora in IBD, but little is known about the complex interactions occurring between pro- and anti-inflammatory cytokines. The central hypothesis will be systematically tested as follows: 1. The role of fMLP in a chronic ¿reactivated¿ model of colitis and its ability to cause reactivation by itself will be investigated (Hypothesis: fMLP can initiate the relapse of inflammation in this model and contribute to the pathogenesis of colitis in the relapse phase.). 2. The levels of various cytokines after administration of fMLP in chronic ¿reactivated¿ colitis will be measured (Hypothesis: If damage is increased by fMLP, then an increase in pro-inflammatory cytokines, or a change in the balance of the immune system, will be observed.). 3. The role of fMLP in the secretory responses and motility changes of the intestine in chronic ¿reactivated¿ colitis will be evaluated (Hypothesis: Alterations of cytokine levels and release of neuromodulators by administration of fMLP in a reactivated model of animal colitis may alter the ion transport processes and contractile responses of the colon, thus contributing to the diarrhea observed in the human condition.). Knowledge of the immunoregulatory pathways evoked in response to bacterial peptides in chronic colitis will provide new avenues for potential therapeutic intervention in the future, and will solve the controversy over the effectiveness of antibiotic treatment.