Membrane-type 1 Matrix Metalloproteinase in COPD

描述(申请人提供)：慢性阻塞性肺疾病(COPD)是一种占很大比例的疾病，也是未来研究的关键目标。具有该领域专业知识的新研究人员的发展将是我们在了解COPD的发病机制和治疗方面取得进展的重要一步。这项拨款提案要求支持我在职业生涯中从一名在肺部疾病的分子和细胞生物学方面拥有知识的临床科学家转变为一名独立的研究员，专注于利用蛋白质酶介导的肺部疾病(如慢性阻塞性肺病)的分子生物学技术。在过去的几十年里，COPD的发展被归因于吸烟引起的炎症和弹性蛋白酶的产生，但最近胶原酶被认为与肺气肿的发展有关。笔者发现，在香烟烟雾致COPD小鼠模型中，肺泡巨噬细胞和呼吸道上皮细胞表达胶原酶-1型基质金属蛋白酶(MT1-MMPs)，在萘诱导的急性呼吸道上皮损伤后的气道中也有表达，提示其在肺损伤修复中起一定作用。基于这些观察，我推测MT1-MMPs参与了COPD的发病机制。我将研究有无MT1-MMP时的肺泡壁破坏、气道重塑、巨噬细胞迁移和炎症，以确定在香烟烟雾暴露期间MT1-MMPs产生的作用和后果。这项申请中提出的工作将在华盛顿大学罗伯特博士的实验室与一个由转基因小鼠技术、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。这是一个已被证明在培养内科科学家从事研究事业方面取得成功的环境。除了揭示COPD治疗的新靶点外，这项提议还将为我的职业发展提供帮助，使我获得独立从事COPD研究的技能。

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.