EPITHELIAL SECRETORY MECHANISMS IN ENTERIC INFECTION

研究者的长期目标是提高对 治疗与肠道感染相关的消化道疾病。在 在计划项目的背景下，本计划中提出的研究目标 单位是为宿主-病原体相互作用提供功能相关性 由其他参与研究者定义。这里提出的研究 将重点放在两个临床上重要的肠道病原体，沙门氏菌和 贾第虫，分别作为侵入性和腔病原体的原型。 有待检验的总体假设是， 这些病原体的感染反映了 上皮分泌、吸收和/或屏障功能，通过 直接作用于上皮细胞以及通过次级细胞类型 调解员。此外，这些影响被提议涉及改变 无论是表达，定位和/或功能的关键运输 以及上皮细胞中的调节蛋白。所有研究将 使用人类衍生的模型系统进行，因为大量物种 众所周知，不同的存在于发展中的疟疾疾病， 对感染的反应。研究将使用还原论者和 细胞系模型以及人肠组织的异种移植物中 在SCID小鼠中维持。这些后者的异种移植，发展成熟的 儿科肠道的特征，允许上皮参数 在一个综合系统中进行评估。因此， 非上皮细胞类型对感染引起的病理的影响， 评估。它们还将允许研究小肠功能， 对于这些细胞系模型并不存在。四个具体目标是 提出了我们将研究感染和致病的影响 （1）氯化物分泌的变化机制，（2）钠偶联 葡萄糖吸收，（3）刷状缘二糖水解，和（4） 对小分子和大分子的屏障功能。研究将包括 电生理学，生物化学和分子方法，并将 由于盐藻的各种突变株的可用性而促进。 总的来说，这些研究应该为病原体诱导的 肠道功能障碍这些研究的结果相应地 预计将对我们的基础和临床意义 对肠上皮的了解。

The long-term goal of the investigator is to improve the understanding and treatment of diarrheal diseases associated with enteric infections. In the context of the Program Project, the goal of the studies proposed in this unit is to provide a functional correlate for host-pathogen interactions defined by other participating investigators. The studies proposed here will focus on two clinically-important enteric pathogens, Salmonella and Giardia, as prototypes of invasive and luminal pathogens, respectively. The overall hypothesis to be tested is that diarrheal illness resulting from infections with these pathogens reflects specific dysfunction of epithelial secretory, absorptive and/or barrier functions, mediated via both direct effects on the epithelium as well as via secondary cell types and mediators. Further, these effects are proposed to involve alterations in either the expression, localization and/or function of key transport and regulatory proteins in the epithelial cells. All studies will be conducted using human-derived model systems given that substantial species differences are known to exist in the development of diarrheal illness in response to infection. Studies will be performed using both reductionist cell line models as well as in xenografts of human intestinal tissue maintained in SCID mice. These latter xenografts, which develop the mature characteristics of pediatric intestine, allow parameters of epithelial function to be assessed in an integrated system. Thus, contributions of non-epithelial cell types to pathology induced by infection can be assessed. They will also allow the study of small intestinal functions, for which adequate cell line models do not exist. Four specific aims are proposed. We will study the effect of infection and pathogenetic mechanisms of changes in (1) chloride secretion, (2) sodium-coupled glucose absorption, (3) brush border disaccharide hydrolysis, and (4) barrier function to small and macro-molecules. The studies will encompass electrophysiological, biochemical and molecular approaches and will be facilitated by the availability of various mutant strains of salmonella. In total, the studies should define paradigms for pathogen-induced intestinal dysfunction. The findings from these studies are accordingly expected to have both basic and clinical implications for our understanding of the intestinal epithelium.