Mucosal Immune Barrier in Infection and Inflammation

描述(申请人提供)：暴露的粘膜表面，如呼吸道、胃肠道和泌尿生殖道表面，主要由单层上皮细胞构成。这一细胞层在粘膜免疫系统中至少有两个主要功能。首先，它是阻止95%通过粘膜表面进入的感染性病原体进入的屏障，也是阻止过敏原和其他有害病原体进入的屏障。粘膜传染病包括艾滋病和其他性传播疾病等高度优先的病原体、大量的机会性感染以及新出现和再次出现的疾病，以及生物恐怖分子病原体。其次，作为对这些病原体的反应，炎性细胞和免疫细胞被招募并穿过上皮屏障，遵循趋化梯度。该计划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。项目和核心领导结合了丰富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整个动物，尽管我们专注于肺上皮作为典型的粘膜，铜绿假单胞菌作为典型的粘膜病原体。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，以保持其完整性。项目1集中在上皮伤口愈合的基本机制上。项目2的重点是铜绿假单胞菌是如何改变伤口愈合的，与项目1非常相似。项目3和项目4的重点是炎症细胞穿过上皮单分子层进入管腔的运动。项目3考虑了中性粒细胞的迁移，特别是CD47和Mac-L的配体的作用。项目4的重点是基质金属蛋白酶(MMPs)在炎症细胞进入管腔的趋化作用中的作用。所有四个项目都得到了所有三个核心的支持。核心A是行政管理。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焦成像，这将是所有项目的关键。通过OUT有非常广泛的互动和合作。例如，项目1、2和4都对某些MMP使用了被敲除的老鼠。

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.