Genomic Approaches to Host-Pathogen Interactions

描述(申请人提供)：肠道上皮屏障和粘膜免疫系统检测并对肠道抗原做出反应。这种反应从耐受性到居民共生性，再到对病原体的主动免疫反应，不一而足。更好地了解肠道微生物区系和肠道粘膜之间的相互作用，应该有助于深入了解肠道炎症的发病机制。工作中的基本假设是：1)病原体独特地改变肠粘膜中的基因表达，肠粘膜中的特定受体负责启动宿主细胞反应；2)核因子-kappaB的激活功能是天然免疫和获得性免疫激活途径的结点；3)除了引发转录反应外，肠道微生物还可以诱导肌动蛋白细胞骨架的巨大变化。拟议的研究将集中在我们实验室熟悉的模型系统上。作为这一提议的初步研究的一部分，我们已经建立并测试了一种表达克隆策略，该策略能够识别病原体响应宿主转录因子的已知和新的激活物。 为实现这些目标，本提案的具体目标是： 具体目的I：确定有助于宿主细胞对细菌的核因子-kappaB反应的信号分子。 特定目的II：描述介导宿主细胞肌动蛋白细胞骨架变化的分子通路。 这项研究计划的长期目标是确定与免疫、炎症和宿主对肠道炎症的抵抗力相关并影响其的蛋白质。

DESCRIPTION (provided by applicant): The intestinal epithelia barrier and the mucosal immune system detect and respond to intestinal antigens. This response varies from tolerance to resident commensals an active immune response to pathogens. A better understanding of the interaction between intestinal microflora and the intestinal mucosa should provide insight into the pathogenesis of intestinal inflammation. The underlying hypotheses at work are 1) pathogens uniquely alter gene expression in the intestinal mucosa and specific receptors in the intestinal mucosa are responsible for initiating host cell responses 2) NF-kappaB activation functions as a nodal point for pathways activated by innate and adaptive immunity 3) In addition to eliciting transcriptional responses intestinal microbes induce dramatic changes in the actin cytoskeleton. The proposed research will focus on model systems familiar to our laboratory. As part of our preliminary studies for this proposal, we have established and tested an expression cloning strategy capable of identifying known and novel activators of pathogen responsive host transcription factors. To accomplish these goals, the specific aims of this proposal are: Specific Aim I: To identify signaling molecules that contribute to the host cell NF-kappaB response to bacteria. Specific Aim II: To delineate molecular pathways that mediate host cell actin cytoskeletal changes in response to bacteria. The long term goals of this research program is to identify proteins associated with and that influence immunity, inflammation and host resistance to intestinal inflammation.