Significance of Luminal Exosomes in Inflammatory Bowel Disease (IBD)

 描述(由申请人提供)：细胞生物学的最新进展报告了细胞外小泡(EV)在细胞-细胞信号传递中的作用。这些是可以从细胞中脱落的细胞内容(如RNA)的小包，并反映了原始细胞的特征。癌症研究表明，这些EV是肿瘤细胞的有用标记，是清除癌症药物和影响周围细胞的一种机制。尽管它们作为异常细胞类型的标志在临床上很有趣，但EVS影响邻近细胞活性的能力在我们理解疾病过程中具有重要的潜在意义。在炎症条件下，从局部细胞释放的EV可能具有免疫调节和药物清除的特性。在炎症性肠病(IBD)患者中，潜在的慢性肠道炎症表现出不同的位置和严重程度随着时间的推移。目前监测疾病活动的手段受到成本、并发症或特异性(例如CT、结肠镜检查)的限制。申请者的K23资助项目的初步工作已经从活动期结肠炎患者的肠腔中分离出EV。这些细胞信号载体保护它们的RNA和蛋白质含量不被降解，使它们适合在粪便样本中检测。该应用程序建议从IBD患者和健康对照组获取肠液、粪便和组织样本，以测试它们是否存在EVS，并根据含量和表面标记描述它们的特征。这项研究将比较从活动性疾病患者和非活动性疾病患者的肠道分离出的EVS的水平和含量，作为疾病活动性的比较。它还将确定粪便样本是否反映从肠腔中分离出来的EVS的含量。此外，本研究还将测量这些分离的EV对培养的肠上皮细胞的影响，以确定是否 它们改变了这些细胞的基因表达模式和趋化特性。这项提议将产生初步数据，以支持进一步研究管腔EV作为疾病活动的标志物以及整个肠道的介体或炎症信号的作用。分泌型EVS对肠道微生物组的组成和功能的影响也计划在未来的研究中进行。

 DESCRIPTION (provided by applicant): Recent advances in cell biology have reported a role for extracellular vesicles (EVs) in cell-cell signaling. These are small 'packets' of cellular contnt (such as RNA) that can be shed from cells, and reflect the characteristics of the originating cells Studies in cancer have shown these EVs to be useful markers of neoplastic cells, and are a mechanism to clear cancer drugs and influence surrounding cells. Although their use as a signature of abnormal cell types is clinically interesting, the ability of EVs to influence the actvity of neighboring cells is of great potential significance in our understanding of disease processes. In inflammatory conditions, EVs released from local cells could have immune modulating, and drug clearance, properties. In patients with Inflammatory Bowel Disease (IBD), the underlying chronic intestinal inflammation exhibits variations in both location and severity over time. Contemporary means of monitoring disease activity are limited by costs, complications or specificity (e.g. CT, colonoscopy). Preliminary work from the applicant's K23-funded project has isolated EVs from the intestinal lumen of patients with active colitis. These cellular signaling vehicles preserve their RNA and protein content from degradation, making them suitable for detection in fecal samples. This application proposes to obtain intestinal fluid, fecal and tissue samples from patients with IBD, and healthy controls, to test them for the presence of EVs, and describe their characteristics based on content and surface markers. The study will compare levels, and content of, EVs isolated from the intestinal tract between patients with active and inactive disease as a disease activity comparator. It will also determine whether fecal samples reflect the content of EVs that are isolated from the intestinal lumen. In addition, this study wil measure the effect of these isolated EVs on intestinal epithelial cells in culture, to determine if they alter the gene expression patterns and chemotactic properties of these cells. This proposal would generate preliminary data to support further examining the role of luminal EVs as markers of disease activity, and mediators or inflammatory signals throughout the intestinal tract. The impact of secreted EVs on the composition and function of the intestinal microbiome is also planned in future studies.