Membrane-type 1 Matrix Metalloproteinase in COPD

慢性阻塞性肺疾病（COPD）是一种占主要比例的疾病，也是治疗的关键目标。 未来的研究。培养在这一领域具有专门知识的新的调查人员将是重要的一步， 我们对COPD的发病机制和治疗的理解取得了进展。这份拨款申请 请求支持我的职业生涯从一个具有分子和生物学知识的临床科学家过渡， 将肺部疾病的细胞生物学转化为独立的研究者，重点是利用分子生物学 技术在蛋白酶介导的肺部疾病，如COPD。在过去的几十年里， COPD的发展归因于香烟烟雾诱导的炎症和弹性蛋白酶 但是最近胶原酶被认为与肺气肿的发展有关。我发现 膜型基质金属蛋白酶（MT 1-MMP）是一种胶原酶， 巨噬细胞和气道上皮细胞在香烟烟雾暴露诱导的COPD和 在萘诱导的急性气道上皮损伤后的气道中，提示其在肺损伤中起作用 和修复。基于这些观察，我推测MT 1-MMP参与了 慢性阻塞性肺病我将检查肺泡壁破坏，气道重塑，巨噬细胞迁移和炎症 在存在和不存在MT 1-MMP的情况下，以确定MT 1-MMP产生的作用和后果 这是在吸烟时发生的。本申请中提出的工作将在 华盛顿大学高级罗伯特博士实验室与咨询委员会合作 由转基因小鼠技术、上皮细胞生物学和细胞外 矩阵这是一个环境，已被证明是成功的医生科学家的发展， 研究生涯。除了发现治疗COPD的新靶点外，该提案还将 提供职业发展，使我能够独立进行COPD研究。

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.