Mucosal Immune Barrier in Infection and Inflammation

描述（由申请人提供）：暴露的粘膜表面，如呼吸道、胃肠道和泌尿生殖系统表面，主要由单层上皮细胞排列。这个细胞层在粘膜免疫系统中至少有两个主要功能。首先，它是屏障，防止95%的感染因子通过粘膜表面进入腹腔，同时也是屏障，防止过敏原和其他有害因子进入腹腔。粘膜传染病包括艾滋病和其他性传播疾病、许多机会性感染和新出现和再出现的疾病以及生物恐怖主义病原体等高度优先的病原体。其次，在对这些病理因子的反应中，炎症细胞和免疫细胞被招募并沿着趋化梯度穿过上皮屏障。这个项目提出了一个多学科和高度互动的方法来解决这些问题。项目和核心领导者结合了大量的经验和不同的见解和技术。我们的实验系统范围从体外细胞培养到转基因全动物，尽管我们专注于肺上皮作为示范性粘膜，铜绿假单胞菌作为示范性粘膜病原体。上皮单层的完整性对其粘膜免疫功能至关重要。上皮单层具有复杂的伤口愈合机制来维持其完整性。项目1主要研究上皮性伤口愈合的基本机制。项目2关注的是铜绿假单胞菌如何改变伤口愈合，并与项目1密切相关。项目3和4关注炎症细胞穿过上皮单层进入管腔的运动。项目3考虑了多形核中性粒细胞的转运，特别是CD47和mac - 1配体的作用。项目4的重点是基质金属蛋白酶（MMPs）在炎症细胞趋化进入管腔中的作用。所有四个项目都由所有三个核心支持。核心A是管理。核心B，细胞分离和培养，为所有项目提供原代肺上皮细胞。核心C提供活细胞多光子和共聚焦成像，这将是至关重要的所有项目。整个过程中都有非常广泛的互动和合作。例如，项目1、项目2和项目4都利用敲除特定MMPs的小鼠。

DESCRIPTION (provided by applicant): Exposed mucosal surfaces, such as the respiratory, gastrointestinal, and genitourinary surfaces, are lined primarily by a single layer of epithelial cells. This cell layer serves at least two primary functions in the mucosal immune system. First, it is a barrier to the entry of the >95% of infectious agents that enter through mucosal surfaces, as well as a barrier to allergens and other noxious agents. Mucosal infectious diseases include such high priority agents as AIDS and other sexually transmitted diseases, numerous opportunistic infections and emerging and re-emerging diseases, and bio-terrorist agents. Second, in response to these pathologic agents, inflammatory and immune cells are recruited and cross the epithelial barrier, following a chemotactic gradient. This Program Project presents a multidisciplinary and highly interactive approach to these problems. The Project and Core leaders combine a great deal of experience and diverse insights and techniques. Our experimental systems range from in vitro cell culture to genetically modified whole animals, though we focus on lung epithelium as an exemplary mucosal, and Pseudomonas aeruginosa as an exemplary mucosal pathogen. The integrity of the epithelial monolayer is essential to its mucosal immune function. The epithelial monolayer has sophisticated wound-healing mechanisms to maintain its integrity. Project 1 concentrates on the basic mechanisms of epithelial wound healing. Project 2 focuses on how wound healing is altered by P. aeruginosa and closely parallels Project 1. Projects 3 and 4 focus on the movement of inflammatory cells across the epithelial monolayer into the lumen. Project 3 considers the transmigration of the polymorphonuclear neutrophil, specifically the role of CD47 and the ligand for Mac-l. Project 4 focuses on the role of matrix metalloproteases (MMPs) in chemotaxis of inflammatory cells into the lumen. All four projects are supported by all three cores. Core A is administrative. Core B, Cell Isolation and Culture, provides primary lung epithelial cells for all projects. Core C provides Live Cell Multiphoton and Confocal Imaging, which will be vital to all projects. There is very extensive interaction and collaboration through out. For instance, Projects 1, 2 and 4 all utilize mice knocked-out for certain MMPs.