GIARDIAL CROSSTALK WITH THE HUMAN INTESTINAL EPITHELIUM

贾第虫与人类肠上皮的串扰

• 批准号: 6438192
• 负责人: FRANCES D. GILLIN
• 金额: $ 22.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6438192
• 关键词: Giardia; cell adhesion; cell cell interaction; cell differentiation; cytoskeleton; enzyme linked immunosorbent assay; gastrointestinal epithelium; gel electrophoresis; giardiasis; host organism interaction; interferon gamma; intracellular parasitism; mucosal immunity; parasitic gastrointestinal disorder; phosphorylation; tissue /cell culture; transmission electron microscopy; virulence; xenotransplantation

Giardia lamblia is a major cause of diarrheal disease worldwide, yet little is known of its mechanisms of pathogenesis. Trophozoites are not known to invade, express any virulence factor, or elicit an inflammatory response. Therefore, it is crucial to understand giardial interactions with the intestinal epithelium from both the parasite and the host perspective. The overall goal of this Unit is to elucidate the molecular, cellular, and biochemical cross talk between giardial trophozoites and human intestinal epithelial cells in vitro and in a human intestinal xenograft model. The underlying hypothesis is that physiologic stimuli from host epithelial cells may modulate giardial behavior and enable trophozoites to better colonize and evade natural host defenses. Conversely, attachment of trophozoites may elicit physiologically relevant responses to the host epithelial barrier. We will determine whether the cross talk is due to giardial attachment to live cells or caused by factors released into the environment. Aim 1 is to investigate trophozoite survival., growth, and attachment responses to cultured human intestinal epithelial cells. Aim 2 is to test the hypothesis that exposure to epithelial cells or signals from them may: A. cause encysting trophozoites to revert from differentiation to growth; B. change overall trophozoite development programs as manifested by alterations in protein, protein phosphorylation, and mRNA fingerprints; C. induce expression of giardial virulence factors. Aim 3 is to test the hypothesis that attachment will induce changes in the cytoskeleton and ultrastructure of both trophozoites and intestinal epithelial cells that may give key insights into their interactions. Aim 4 is to evaluate the human intestinal xenograft model as a system to study the response of normal intestinal epithelial cells to giardial colonization. This system will allow us to define both host and parasite factors required for infection. These studies will greatly extend our understanding of an important intestinal parasite and have the potential to yield new insights into intestinal barrier and defense functions.

贾第鞭毛虫是全世界腹泻病的主要原因，但 对其发病机制知之甚少。滋养体不是 已知会侵入、表达任何毒力因子或引发炎症 回复。因此，了解贾第虫相互作用至关重要 具有来自寄生虫和宿主的肠上皮 看法。本单元的总体目标是阐明分子、 贾第鞭毛虫滋养体之间的细胞和生化交叉对话 体外和人肠道中的人肠上皮细胞 异种移植模型。基本假设是生理刺激 来自宿主上皮细胞的可能调节贾第虫行为并使得 滋养体更好地定植并逃避宿主的自然防御。 相反，滋养体的附着可能会引起生理相关的 对宿主上皮屏障的反应。我们将确定是否 串扰是由于贾第虫附着在活细胞上或由以下原因引起的 释放到环境中的因子。目标 1 是研究滋养体 对培养的人类肠道的生存、生长和附着反应 上皮细胞。目标 2 是检验以下假设： 上皮细胞或来自它们的信号可能： A. 导致滋养体包囊 从分化恢复到增长； B.改变整体滋养体 发展计划表现为蛋白质、蛋白质的改变 磷酸化和 mRNA 指纹； C.诱导贾第虫的表达 毒力因素。目标 3 是检验依恋会影响这一假设 诱导两个滋养体的细胞骨架和超微结构的变化 和肠上皮细胞，这可能会给他们提供重要的见解 互动。目标 4 是评估人类肠道异种移植模型 研究正常肠上皮细胞反应的系统 贾第虫殖民化。该系统将允许我们定义主机和 感染所需的寄生虫因子。 这些研究将极大地扩展我们对一个重要领域的理解 肠道寄生虫并有可能产生新的见解 肠道屏障和防御功能。