EPITHELIAL SECRETORY MECHANISMS IN ENTERIC INFECTION

调查员的长期目标是提高对 与肠道感染相关的腹泻疾病的治疗。在 方案项目的背景、本报告中提出的研究目标 单元是为宿主与病原体的相互作用提供功能关联 由其他参与调查人员定义。在这里提出的研究 将重点关注两种临床上重要的肠道病原体，沙门氏菌和 贾第鞭毛虫，分别作为侵袭性病原体和腔性病原体的原型。 需要检验的总体假设是腹泻病导致 从这些病原体的感染反映出特定的功能障碍 上皮分泌、吸收和/或屏障功能，通过 对上皮的直接作用以及对次级细胞类型的影响 和调解人。此外，这些影响被认为涉及到改变 在密钥传输的表达、定位和/或功能中 以及上皮细胞中的调节蛋白。所有的研究都将是 使用人类衍生的模型系统进行，假设有大量物种 已知在腹泻病的发生方面存在差异 对感染的反应。将使用两种简化论者进行研究 人肠道组织异种移植模型和细胞系模型的建立 在SCID小鼠体内维持。后一种异种移植物发育成成熟的 儿科肠道的特点，允许上皮性参数 将在集成系统中评估的功能。因此，以下方面的贡献 非上皮细胞类型可由感染引起的病理改变 评估过了。它们还将允许研究小肠功能， 没有足够的细胞系模型可供选择。四个具体目标是 建议。我们将研究感染和致病的影响 (1)氯化物分泌，(2)钠偶联的变化机制 葡萄糖吸收，(3)刷状边缘二糖水解，和(4) 对小分子和大分子起屏障作用。这些研究将包括 电生理、生化和分子方法，并将是 各种沙门氏菌突变株的可获得性促进了这一进程。 总而言之，这些研究应该确定病原体诱导的范例 肠道功能障碍。因此，这些研究的发现如下 预计将对我们的 对肠道上皮的了解。

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.