Role of Metalloproteinases in Mucin Overproduction in COPD

金属蛋白酶在慢性阻塞性肺病粘蛋白过量产生中的作用

基本信息

批准号：
7461274
负责人：
George Douglas Leikauf
金额：
$ 35.32万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7461274
关键词：
Acrolein Acute Animal Model Binding Breathing CD44 gene Cause of Death Cell physiology Cell-Free System Cells Chronic Chronic Obstructive Airway Disease Cigarette Clara cell Complex Condition Dominant-Negative Mutation Environmental Irritants Epidermal Growth Factor Epidermal Growth Factor Receptor Epithelial Epithelial Cells Epithelium Erlotinib Event Family Future Gelatinase B Gene Expression Gene Targeting Genetic Transcription Goals Growth Factor Receptors Health Human In Vitro Intervention Irritants Knowledge Lead Ligand Binding Ligands Lung diseases MAP Kinase Gene MMP9 gene MUC5AC gene Mass Spectrum Analysis Matrix Metalloproteinases Measures Mediating Membrane Messenger RNA Metalloproteases Molecular Mucins Mucous body substance Mus Pathway interactions Phosphorylation Post-Translational Protein Processing Process Production Proprotein Convertases Proteins Receptor Activation Receptor Inhibition Receptor Signaling Regulation Research Resistance Role Signal Pathway Signal Transduction Small Interfering RNA Smoke Therapeutic Therapeutic Intervention Time Tissue Inhibitor of Metalloproteinases Transcript Work airway epithelium base cigarette smoke-induced cigarette smoking cigarette smoking human MMP14 protein in vivo inhibitor/antagonist innovation insight intracellular protein transport prevent protein transport response

项目摘要

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.

描述（由申请人提供）：问题。慢性阻塞性肺病（COPD）是第四大死因，显然是由吸烟和其他环境刺激物引起的。 COPD 的一个特征涉及气道上皮的表型转变，其特征是纤毛细胞和克拉拉细胞减少以及粘液产生细胞增加。重要的是，香烟烟雾中的刺激物，特别是丙烯醛，可以引发这些事件。尽管基质金属蛋白酶 (MMP) 在 COPD 中的可能作用已得到广泛认可，但 MMP 激活如何协调上皮细胞功能持续变化的机制尚不确定。因此，该提案的总体目标是确定激活 MMP/上皮生长因子受体 (EGFR) 信号传导的分子机制，从而导致持续的粘液过量产生。假设：丙烯醛/香烟烟雾最初会激活 MMP，从而增加粘蛋白转录。此外，长期暴露会进一步刺激 MMP 的转录，并抑制金属蛋白酶组织抑制剂的转录。这些即时反应和延迟反应相结合，导致粘液持续产生。目标。确定控制以下的分子机制：1) 气道上皮细胞中 MMP14 激活/表达增加，2) 气道上皮细胞中 MMP9 激活/表达增加，以及 3) 小鼠粘蛋白产生中的 MMP14/MMP9/EGFR 信号传导。意义。该提案旨在建立吸入刺激物激活调节粘蛋白基因表达的信号通路的机制。该项目完成后，我们希望更好地了解丙烯醛或香烟烟雾如何 1) 激活 MMP14，2) 修改控制持久性 MMP9 转录的细胞信号传导，3) 调节小鼠气道中急性和持久的粘蛋白产生， 4) 产生一种持续产生粘蛋白的机制，可以通过抑制前蛋白转化酶/EGFR 来阻止这种机制。项目叙述。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（MMP）并启动控制持久粘蛋白产生的事件的机制。该项目完成后，我们期望：1) 更好地了解丙烯醛激活人气道上皮细胞中 MMP14 的机制，2) 了解丙烯醛修改控制持续 MMP9 产生的细胞信号传导的机制/体外激活和粘蛋白产生，3) 鉴定香烟烟雾和丙烯醛暴露的动物模型气道中急性和持续粘蛋白产生的调节事件，以及 4)确定蛋白转化酶/EGFR 抑制剂是否可以预防导致持续粘蛋白产生的事件。这项研究对人类健康的预期影响是基于证据的科学验证或驳斥针对 MMP14/MMP9/EGFR 信号传导的疗法可考虑用于治疗 COPD 粘液过度产生的可能性。