Role of Metalloproteinases in Mucin Overproduction in COPD

描述(申请人提供)：问题。慢性阻塞性肺疾病(COPD)是第四大死亡原因，显然是由吸烟和其他环境刺激物引起的。COPD的一个特征是呼吸道上皮细胞的表型转变，其特征是纤毛细胞和Clara细胞减少，粘液产生细胞增加。重要的是，香烟烟雾中的刺激物，特别是丙烯醛，可以触发这些事件。尽管基质金属蛋白酶(MMPs)在慢性阻塞性肺疾病(COPD)中的可能作用已被充分认识，但其激活如何协调上皮细胞功能的持续变化的机制尚不清楚。因此，这项建议的总体目标是确定激活MMPs/上皮生长因子受体(EGFR)信号进而导致持续粘液过度生产的分子机制。假设：丙烯醛/香烟烟雾最初激活MMPs，从而增加粘蛋白转录。此外，慢性暴露进一步刺激MMPs的转录，并抑制金属蛋白酶组织抑制物的转录。这些即时和延迟的反应结合在一起，会导致持续的粘液产生。目标。探讨MMP14在小鼠呼吸道上皮细胞中的激活/表达，MMP9在呼吸道上皮细胞中的激活/表达，以及MMP14/MMP9/EGFR信号转导在小鼠粘蛋白产生中的作用。意义重大。这项提议试图建立吸入刺激物激活信号通路以调节粘蛋白基因表达的机制。在这个项目完成后，我们希望更好地了解丙烯醛或香烟烟雾如何激活MMP14，2)修改控制持久MMP9转录的细胞信号，3)调节小鼠呼吸道急性和持久粘蛋白的产生，以及4)产生可通过抑制原蛋白转换酶/EGFR抑制的持久粘蛋白产生的机制。项目叙事。这项研究具有重要意义和创新性，因为它将确定丙烯醛和香烟烟雾激活基质金属蛋白酶(MMPs)并启动控制持久粘蛋白产生的事件的机制。在该项目完成后，我们期望：1)更好地了解丙烯醛激活人呼吸道上皮细胞MMP14的机制；2)了解丙烯醛修饰细胞信号转导机制以控制体外持久的MMP9产生/激活和粘蛋白产生的机制；3)识别在香烟烟雾和丙烯醛暴露的动物模型中调节急性和持久粘蛋白产生的事件；以及4)确定蛋白转换酶/EGFR抑制剂是否可以防止导致持久粘蛋白产生的事件。这项研究预期的人类健康影响是基于证据的科学验证或驳斥针对MMP14/MMP9/EGFR信号转导的疗法可被考虑用于治疗COPD粘液过度生产的可能性。

DESCRIPTION (provided by applicant): Problem. Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death, is clearly caused by cigarette smoking and other environmental irritants. One feature of COPD involves a phenotypic shift in the airway epithelium characterized by decreased ciliated and Clara cells and increased mucus producing cells. Importantly, irritants in cigarette smoke, particularly acrolein, can trigger these events. Although the possible roles of matrix metalloproteinases (MMPs) in COPD are well recognized, the mechanisms of how MMP-activation orchestrates a persistent change in epithelial cell function are uncertain. Thus, the overall objective of this proposal is to determine the molecular mechanisms activating MMPs/epithelial growth factor receptor (EGFR) signaling that in turn lead to persistent mucus overproduction. Hypothesis: Acrolein/cigarette smoke initially activates MMPs that increase mucin transcription. In addition, chronic exposure further stimulates transcription of MMPs, and represses transcription of tissue inhibitors of metalloproteinase. Combined, these immediate and delayed responses lead to persistent mucus production. Aims. To determine the molecular mechanisms controlling: 1) increased MMP14 activation/ expression in airway epithelial cells, 2) increased MMP9 activation/expression in airway epithelial cells, and 3) MMP14/MMP9/ EGFR-signaling in mucin production in mice. Significance. This proposal seeks to establish the mechanisms by which inhaled irritants activate signaling pathways that regulate mucin gene expression. At the completion of this project, we expect to obtain a better understanding of how acrolein or cigarette smoke 1) activates MMP14, 2) modifies cell signaling that controls persistent MMP9 transcription, 3) modulates acute and persistent mucin production in the airways of mice, and 4) generates a mechanism to persistent mucin production that can be prevented by proprotein convertase/ EGFR inhibition. PROJECT NARRATIVE. This research is significant and innovative because it will determine the mechanisms by which acrolein and cigarette smoke can activate matrix metalloproteinases (MMPs) and initiate events controlling persistent mucin production. At the completion of this project, we expect: 1) to obtain a better understanding of the mechanisms by which acrolein activates MMP14 in human airway epithelial cells, 2) to gain knowledge into the mechanism by which acrolein modifies cell signaling that controls persistent MMP9 production/activation and mucin production in vitro, 3) to identify the events modulated in acute and persistent mucin production in the airways of an animal model of cigarette smoke and acrolein exposure, and 4) to determine whether protein convertase/EGFR inhibitors can prevent the events that leads to persistent mucin production. The anticipated human health impact of this study is an evidence-based scientific verification or refutation of the likelihood that therapeutics directed at MMP14/MMP9/EGFR signaling can be considered for the treatment of mucus overproduction in COPD.