Polymicrobial induction of epithelial inflammation

描述（由申请方提供）：上皮细胞通过感知细菌产物和将中性粒细胞募集到粘膜表面，作为先天免疫系统的最近端。在定殖过程中，这些细胞同时暴露于大量的微生物产物，并且还不清楚这些组合如何改变上皮细胞的反应。本文提供的初步数据描述了一种在多微生物刺激环境中产生炎症的新系统。同时暴露于两种重要的人类呼吸道病原体，S。pneumoniae和H.流感病毒诱导上皮细胞协同产生促炎细胞因子。这种作用在体外和体内都发生，并与中性粒细胞募集有关。本建议旨在描述这种反应的机制。第一个具体的目标将解决的假设，特定的细菌成分，从S。pneumoniae和H.流感是协同诱导炎症所必需和充分的。第二个具体目标是解决参与该途径的特定宿主分子机制。这些研究有可能进一步了解目前的免疫反应，在殖民化的粘膜表面，与殖民化和侵袭性疾病的影响。 本申请描述了一个程序，旨在为亚当·拉特纳博士提供必要的技能，成为微生物发病机理的独立调查员。拉特纳博士已经完成了儿科传染病的奖学金培训，并将由呼吸道疾病发病机制专家杰弗里·韦泽博士指导。该计划包括遗传学，免疫学和细菌发病机理领域的教学研究。此外，深入的实验室经验将使Ratner博士接触细胞生物学，生物化学，生理学和分子生物学领域的各种技术，从而为开始独立的研究生涯奠定坚实的基础。

DESCRIPTION (provided by applicant): Epithelial cells act as the most proximal arm of the innate immune system by sensing bacterial products and recruiting neutrophils to mucosal surfaces. During colonization, these cells are concurrently exposed to a vast array of microbial products, and it is not well understood how these combinations may alter the responses of epithelial cells. Preliminary data presented here describe a novel system for the generation of inflammation in the setting of polymicrobial stimulation. Concurrent exposure to two important human respiratory pathogens, S. pneumoniae and H. influenzae, induces synergistic production of proinflammatory cytokines by epithelial cells. This effect occurs both in vitro and in vivo and is associated with neutrophil recruitment. This proposal is designed to characterize the mechanism of this response. The first specific aim will address the hypothesis that specific bacterial components from S. pneumoniae and H. influenzae are necessary and sufficient for synergistic induction of inflammation. The second specific aim addresses specific host molecular mechanisms involved in this pathway. These studies have the potential to further the current understanding of immune responses at colonized mucosal surfaces, with implications for both colonization and invasive disease. This application describes a program designed to provide Dr. Adam Ratner with the skills necessary to become an independent investigator in microbial pathogenesis. Dr. Ratner has completed fellowship training in pediatric infectious diseases and will be mentored by Dr. Jeffrey Weiser, an expert in the pathogenesis of respiratory diseases. The program includes didactic study in the areas of genetics, immunology, and bacterial pathogenesis. In addition, an in-depth laboratory experience will expose Dr. Ratner to a wide variety of techniques in the areas of cell biology, biochemistry, physiology, and molecular biology, thus providing a solid foundation for beginning an independent research career.