Membrane-type 1 Matrix Metalloproteinase in COPD

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是一种占主要比例的疾病，也是未来研究的关键目标。发展具有该领域专业知识的新研究者将是我们理解COPD发病机制和治疗的重要一步。这项拨款申请要求支持我从一名具有肺部疾病分子和细胞生物学知识的临床科学家转变为一名独立的研究者，专注于利用蛋白酶介导的肺部疾病（如COPD）的分子生物学技术。在过去的几十年里，COPD的发展一直被归因于香烟烟雾诱导的炎症和弹性蛋白酶的产生，但最近胶原酶已被牵连在肺气肿的发展。我已经发现，膜型1基质金属蛋白酶（MT 1-MMP），胶原酶，表达的肺泡巨噬细胞和气道上皮细胞在小鼠模型的香烟烟雾暴露诱导的COPD和在气道萘诱导的急性气道上皮损伤后，表明它在肺损伤和修复中发挥作用。基于这些观察，我推测MT 1-MMP参与COPD的发病机制。我将检查肺泡壁破坏，气道重塑，巨噬细胞迁移和炎症的存在和不存在的MT 1-MMP，以确定的作用和后果的MT 1-MMP生产过程中发生的香烟烟雾暴露。本申请中提出的工作将在华盛顿大学Robert Senior博士的实验室与由转基因小鼠技术、上皮细胞生物学和细胞外基质领域的专家组成的咨询委员会一起进行。这是一个环境，已被证明是成功的医生科学家的研究事业的发展。除了发现治疗COPD的新目标外，该提案还将提供职业发展，使我能够独立进行COPD研究。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a disease of major proportion and a critical target for future research. The development of new investigators with expertise in ths field will be an essential step in progress towards our understanding of the pathogenesis and treatment of COPD. This grant proposal requests support for the transition in my career from a clinical scientist with knowledge in molecular and cellular biology of lung disorders into an independent investigator with a focus in utilizing molecular biology techniques in protease-mediated lung disorders, such as COPD. For the past several decades, the development of COPD has been attributed to cigarette smoke induced-inflammation and elastase production, but recently collagenases have been implicated in the development of emphysema. I have found that membrane-type 1 matrix metalloproteinase (MT1-MMP), a collagenase, is expressed by alveolar macrophages and airway epithelial cells in a mouse model of cigarette smoke exposure induced-COPD and in the airway after naphthalene-induced acute airway epithelial injury, suggesting it plays a role in lung injury and repair. Based on these observations, I hypothesize that MT1-MMP is involved in the pathogenesis of COPD. I will examine alveolar wall destruction, airway remodeling, macrophage migration and inflammation in the presence and absence of MT1-MMP to determine the role and consequences of MT1-MMP production that occurs during cigarette smoke exposure. The work proposed in this application will be performed at Washington University in the laboratory of Dr. Robert Senior in conjunction with an Advisory Committee composed of experts in the fields of transgenic mouse technologies, epithelial cell biology and extracellular matrix. This is an environment that has proven successful in the development of physician scientists for research careers. In addition to uncovering a novel target in the treatment of COPD, this proposal will provide career development, so that I will attain skills to do COPD research independently.