Mechanisms in the Remodeling of Lung Structure

描述（由申请人提供）：本申请是本项目的续篇申请，提出了一个由四个项目和三个核心组成的多学科项目，旨在研究病毒和吸入毒素诱导的肺损伤背景下上皮源性基质分子和蛋白酶、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（层粘连蛋白-5）、表面活性剂蛋白D （SP-D）、基质溶素（MMP-7）、舍甘氨酸和不同的非b -非t （NBNT）淋巴样细胞群。主要的假设是：(1)laminin-332通过对上皮细胞的影响在肺泡和气道损伤的应答中起关键作用；(2) SP-D参与气道对RNA病毒的防御，SP-D表达的改变有助于病毒后气道重塑；(3)硫酸软骨素E链与母体溶素前体相互作用是母体溶素激活的重要途径；(4)呼吸道病毒感染后，不同的NBNT淋巴样细胞群参与了粘膜细胞化生。本研究将仙台病毒、香烟烟雾和萘诱导的小鼠气道和肺泡损伤模型与最先进的上皮培养系统、转基因和基因靶向小鼠、遗传和糖基阵列技术以及晶体学分析相结合。形态学核心/细胞培养核心用于形态学处理和呼吸道上皮细胞的分离和维持，小鼠核心用于生产转基因和靶向小鼠，用于实施香烟引起的肺损伤和呼吸道病毒感染模型，这将是研究人员进行互补但独立研究的专门中心。该应用程序建立在与肺重塑机制和肺损伤反应相关的长期富有成效的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.