Membrane-type 1 Matrix Metalloproteinase in COPD

描述（申请人提供）：慢性阻塞性肺疾病（Chronic obstructive pulmonary disease， COPD）是一种占比较大的疾病，也是未来研究的关键目标。在这一领域培养具有专业知识的新研究人员将是我们了解慢性阻塞性肺病发病机制和治疗的重要一步。本基金申请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专注于利用分子生物学技术治疗蛋白酶介导的肺部疾病（如COPD）的独立研究者。在过去的几十年里，慢性阻塞性肺病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，但最近胶原酶被认为与肺气肿的发展有关。我发现在香烟烟雾暴露诱导的copd小鼠模型和萘诱导的急性气道上皮损伤后的气道中，肺泡巨噬细胞和气道上皮细胞表达膜型1基质金属蛋白酶（MT1-MMP），这是一种胶原酶，提示其在肺损伤和修复中起作用。基于这些观察，我假设MT1-MMP参与了COPD的发病机制。我将检查在MT1-MMP存在和不存在的情况下肺泡壁破坏、气道重塑、巨噬细胞迁移和炎症，以确定吸烟过程中MT1-MMP产生的作用和后果。本申请中提出的工作将在华盛顿大学Robert Senior博士的实验室进行，并与由转基因小鼠技术、上皮细胞生物学和细胞外基质领域专家组成的咨询委员会一起进行。这种环境已被证明在内科科学家从事研究事业的发展中是成功的。除了发现COPD治疗的新靶点外，这个提案将提供职业发展，使我获得独立进行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.