Mechanisms in the Remodeling of Lung Structure

描述(申请人提供)：本计划是本计划项目的延续申请，提出了一个由四个项目和三个核心组成的多学科计划，旨在研究病毒和吸入性毒素引起的肺损伤背景下的上皮细胞来源的基质分子和蛋白酶、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)、表面活性蛋白D(SP-D)、基质溶素(MMP-7)、丝氨酸甘氨酸和独特的非B非T(NBNT)淋巴样细胞群。主要假说是：(1)层粘连蛋白-332通过对上皮细胞的作用在对肺泡和呼吸道损伤的反应中发挥关键作用；(2)SP-D有助于呼吸道防御RNA病毒，并且SP-D表达的变化有助于病毒后的气道重塑；(3)丝氨酸和基质溶素原的硫酸软骨素E链之间的相互作用构成了基质溶素激活的重要途径；以及(4)不同的NBNT淋巴样细胞群参与了呼吸道病毒感染后粘液细胞的化生。拟议的研究将仙台病毒、香烟烟雾和萘引起的小鼠呼吸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、遗传和血糖阵列技术以及结晶学分析相结合。形态核心/细胞培养核心，用于辅助形态程序以及呼吸道上皮细胞的分离和维护，以及小鼠核心，用于生产转基因和靶向小鼠，以及实施香烟烟雾诱导的肺损伤和呼吸道病毒感染模型，将是研究人员在其补充但独立的研究中的专门中心。这一应用建立在与肺重塑机制和肺损伤反应相关的生产性研究和合作的长期历史基础上。

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.