Genomic Approaches to Host-Pathogen Interactions

描述（由申请人提供）：肠上皮屏障和粘膜免疫系统检测肠道抗原并作出反应。这种反应从对常驻共生菌的耐受到对病原体的主动免疫反应各不相同。更好地了解肠道菌群与肠道黏膜之间的相互作用，有助于深入了解肠道炎症的发病机制。潜在的假设是：1)病原体独特地改变肠黏膜中的基因表达，肠粘膜中的特定受体负责启动宿主细胞反应；2)NF-kappaB激活作为先天免疫和适应性免疫激活途径的节点功能；3)除了引发转录反应外，肠道微生物还诱导肌动蛋白细胞骨架发生剧烈变化。建议的研究将集中在我们实验室熟悉的模型系统上。作为本提案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反应性宿主转录因子的已知和新的激活因子。

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.