THE ROLE OF BACTERIAL PEPTIDES IN CHRONIC INTESTINAL INFLAMMATION

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 尽管经过数十年的研究，炎症性肠病（IBD）的基本致病机制仍然未知。目前有许多治疗方法，但仍然没有治愈克罗恩病和溃疡性结肠炎的方法，其主要症状包括腹痛，溃疡，出血，体重减轻和腹泻。临床观察表明，肠道细菌可能会触发，并可能加剧炎症反应。然而，更有可能的是，IBD的发病机制与任何特定的病原体本身无关，而是与细菌产物有关，其中一些已经在患者的肠道中检测到。 该提议的中心假设是细菌肽如N-甲酰基-甲硫氨酰基-亮氨酰基-苯丙氨酸（fMLP）可以通过促炎细胞因子的基因表达的增加以及通过组织活力的降低和运动性的改变来影响慢性结肠炎复发期的炎性应答。FMLP已在患者的肠道中发现，并且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，失调的免疫应答是针对IBD中的正常细菌植物群的，但对促炎细胞因子和抗炎细胞因子之间发生的复杂相互作用知之甚少。中心假设将被系统地测试如下：1。将研究fMLP在结肠炎慢性再活化模型中的作用及其自身引起再活化的能力（假设：fMLP可在该模型中引发炎症复发，并有助于复发期结肠炎的发病机制）。2.将测量慢性再活化结肠炎中给予fMLP后各种细胞因子的水平（假设：如果fMLP增加了损伤，则将观察到促炎细胞因子的增加或免疫系统平衡的变化）。3.将评价fMLP在慢性再活化结肠炎中肠的分泌反应和运动性变化中的作用（假设：在动物结肠炎的再活化模型中通过给予fMLP改变细胞因子水平和神经调节剂的释放可能改变结肠的离子转运过程和收缩反应，从而导致在人体条件下观察到的腹泻。）。 对慢性结肠炎中细菌肽引起的免疫调节途径的了解将为未来潜在的治疗干预提供新的途径，并将解决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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.