Mechanisms in the Remodeling of Lung Structure

描述（由申请人提供）：该提案是本计划项目的延续申请，提出了一个多学科计划，包括四个项目和三个核心，旨在研究病毒和吸入毒素诱导的肺损伤背景下的上皮衍生基质分子和蛋白酶、宿主防御分子和免疫效应细胞。拟议研究的重点将是层粘连蛋白-332（laminin-5）、表面活性蛋白D（SP-D）、基质溶解素（MMP-7）、sergylycin和不同的非B非T（NBNT）淋巴细胞群。主要假设是：（1）层粘连蛋白-332通过其对上皮细胞的作用在对肺泡和气道损伤的应答中起关键作用;（2）SP-D有助于气道防御RNA病毒，并且SP-D表达的改变有助于病毒后气道重塑;（3）丝氨酸甘氨酸的硫酸软骨素E链和基质溶素前体之间的相互作用构成基质溶素活化的重要途径;和（4）一个独特的NBNT淋巴样细胞群参与呼吸道病毒感染后的粘液细胞化生。拟议的研究结合了联合收割机仙台病毒，香烟烟雾和萘诱导的气道和肺泡损伤的小鼠模型，最先进的上皮细胞培养系统，转基因和基因靶向小鼠，遗传和糖组学阵列技术，和晶体学分析。形态学核心/细胞培养核心用于辅助形态学程序和分离和维持呼吸道上皮细胞，小鼠核心用于生产转基因和靶向小鼠，并用于实施香烟烟雾诱导的肺损伤和呼吸道病毒感染模型，将成为研究者进行互补但独立研究的专门中心。该应用建立在与肺重塑机制和肺损伤反应相关的长期生产性研究和合作的基础上。

DESCRIPTION (provided by applicant): This proposal, which is an application for continuation of this Program Project, presents a multidisciplinary program comprised of four projects and three cores designed to investigate epithelial-derived matrix molecules and proteases, host defense molecules, and immune effector cells in the context of lung injuries induced by viruses and inhaled toxins. Focal points of the proposed studies will be laminin-332 (laminin-5), surfactant protein D (SP-D), matrilysin (MMP-7), serglycin, and a distinct population of non-B non-T (NBNT) lymphoid cells. Major hypotheses are that: (1) laminin-332 plays key roles in responses to alveolar and airway injury via its effects on epithelial cells; (2) SP-D contributes to the airway defense against RNA viruses and that alterations in SP-D expression contribute to post-viral airway remodeling; (3) interactions between the chondroitin sulfate E chains of serglycin and pro-matrilysin constitute an important pathway for matrilysin activation; and (4) a distinct NBNT lymphoid cell population is involved in mucous cell metaplasia following respiratory viral infections. The proposed studies combine murine models of airway and alveolar injury induced by Sendai virus, cigarette smoke and naphthalene with state-of-the art epithelial culture systems, transgenic and gene targeted mice, genetic and glycomic array technologies, and crystallographic analysis. A Morphology Core / Cell Culture Core for assistance with morphologic procedures and for isolation and maintenance of respiratory epithelial cells, and a Mouse Core for production of transgenic and targeted mice and for implementing models of cigarette smoke-induced lung injury and respiratory viral infections, will be specialized centers for the investigators in their complementary, yet independent, studies. This application builds on a long history of productive research and collaboration related to mechanisms of lung remodeling and the response to pulmonary injury.