Mucosal Immune Barrier in Infection and Immunity

描述（由申请人提供）：计划项目概述：这是重新提交的计划项目资助（PPG）申请，用于研究感染和炎症中的粘膜屏障。95%的感染源通过暴露的粘膜表面进入，如呼吸道、胃肠道、乳腺和泌尿生殖道。粘液感染包括细菌性和病毒性肺炎、SARS、TB、AIDS和其他性传播疾病、许多机会性、新出现和重新出现的感染以及生物战剂/恐怖分子制剂。粘膜表面衬有上皮细胞，通常为单层。上皮细胞层是感染因子、过敏原和其他有害抗原进入的主要屏障。从根本上说，上皮层是先天性粘膜免疫系统的最基本组成部分。在这个计划项目中，我们专注于两个广泛的和相互关联的领域，上皮层如何在粘膜免疫保护中发挥其功能，特别强调肺上皮。项目1（Mostov）、项目2（Engel）和项目3（罗森）研究上皮伤口愈合的机制、硫酸酯（修饰硫酸乙酰肝素蛋白聚糖的硫酸酯酶）在上皮对损伤的反应中的作用以及极化细胞与细菌病原体的相互作用。项目4（Werb）的重点是炎症细胞如何穿过上皮屏障进入器官内腔。项目1使用两种新的上皮伤口愈合的三维细胞培养模型。项目2的重点是机会致病菌，铜绿假单胞菌，作为上皮病原体相互作用的模型。项目3研究硫如何参与上皮伤口愈合。项目4的重点是蛋白酶和硫在调节粘膜组织中炎性细胞的募集和迁移中的作用。核心A在行政上支持计划项目。Core B（Matthay）提供单层培养物、三维模型和肺切片中的原代人类和啮齿动物肺上皮细胞，以及小鼠中的功能研究。Core C有一个由四个显微镜组成的阵列，适用于体外研究以及活体麻醉小鼠实验的三维和四维细胞动力学分析。 大多数传染性病原体通过暴露的粘膜表面进入人体。这些表面由上皮细胞排列，最常见的是单层。我们正在研究这种上皮屏障如何保护我们免受感染。

DESCRIPTION (provided by applicant): Overview of Program Project: This is a resubmission of a renewal of a Program Project Grant (PPG) application to study the mucosal barrier in infection and inflammation. Ninety-five percent of infectious agents enter through exposed mucosal surfaces, such as the respiratory, gastrointestinal, mammary and urogenital tracts. Mucosal infections include bacterial and viral pneumonia, SARS, TB, AIDS and other sexually transmitted diseases, numerous opportunistic, emerging and re-emerging infections, and biological warfare/terrorist agents. Mucosal surfaces are lined by epithelial cells, usually in a monolayer. The epithelial cell layer is the principal barrier to entry of infectious agents, allergens and other noxious antigens. Fundamentally, the epithelial layer is the most basic component of the innate mucosal immune system. In this Program Project we focus on two broad and inter-related areas of how the epithelial layer performs its functions in mucosal immune protection, with a particular emphasis on pulmonary epithelium. Projects 1 (Mostov), 2 (Engel) and 3 (Rosen) study mechanisms of epithelial wound healing, the roles of sulfs (sulfatases which modify heparan sulfate proteoglycans) in epithelial response to injury and the interaction of polarized cells with a bacterial pathogen. Project 4 (Werb) is focused on how inflammatory cells cross the epithelial barrier to enter the lumen of the organ. Project 1 uses two novel three dimensional cell culture models of epithelial wound healing. Project 2 focuses on the opportunistic pathogen, Pseudomonas aeruginosa, as a model for epithelial pathogen interaction. Project 3 examines how sulfs participate in epithelial wound healing. Project 4 focuses on the role of proteases and sulfs in regulating inflammatory cell recruitment and migration in mucosal tissues. Core A supports the Program Project administratively. Core B (Matthay) provides primary human and rodent lung epithelial cells in monolayer cultures, three-dimensional models and lung slices, as well as functional studies in mice. Core C has an array of four microscopes suitable for three- and four-dimensional analysis of cell dynamics for in vitro studies as well as experiments in living, anesthetized mice. Most infectious agents enter the body through exposed mucosal surfaces. These surfaces are lined by epithelial cells, most commonly in a single layer. We are studying how this epithelial barrier protects us against infection.