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的一个特征涉及气道上皮的表型转移，其特征是纤毛和克拉拉细胞减少并增加了粘液产生细胞。重要的是，香烟烟雾中的刺激性，尤其是丙烯醛，可以触发这些事件。尽管众所周知，基质金属蛋白酶（MMP）的可能作用是众所周知的，但MMP激活如何策划上皮细胞功能的持续变化的机制尚不确定。因此，该提案的总体目的是确定激活MMP/上皮生长因子受体（EGFR）的分子机制，这又导致持续的粘液过度生产。假设：丙烯醛/香烟烟雾最初激活增加粘蛋白转录的MMP。另外，慢性暴露进一步刺激了MMP的转录，并抑制金属蛋白酶组织抑制剂的转录。这些直接和延迟的反应结合在一起，导致持续的粘液产生。目标。为了确定控制的分子机制：1）在气道上皮细胞中MMP14的激活/表达增加，2）增加气道上皮细胞中MMP9激活/表达增加，3）MMP14/ MMP9/ EGFR - EGFR-SIGNALINGing在小鼠中的粘蛋白产生中。意义。该建议旨在建立吸入刺激物激活调节粘蛋白基因表达的信号传导途径的机制。该项目完成后，我们希望更好地了解丙烯醛或香烟烟雾1）激活MMP14，2）修改控制持续的MMP9转录的细胞信号，3）调节急性和持续的粘蛋白在小鼠气道中的持续生产，以及4）可以通过持续的粘液生产来促进粘液蛋白的转换。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可以激活基质金属蛋白酶（MMP）的机制，并启动控制持续性粘蛋白产生的事件。在完成该项目时，我们希望：1）能够更好地理解丙烯醛在人类气道上皮细胞中激活MMP14的机制，2）获得知识，以使丙烯醛控制细胞信号的机制，以控制控制MMP9的生产/激活和粘液量在烟雾中的生产，并稳定质量的MONTIST MONGITENT MONTIST MONTICET MONTICTINE MMP9的生产，3）烟雾和丙烯醛暴露，以及4）确定蛋白转化酶/EGFR抑制剂是否可以防止导致持续性粘蛋白产生的事件。这项研究的预期人类健康影响是一种基于证据的科学验证或反驳针对MMP14/MMP9/EGFR信号的治疗剂的可能性，可以考虑用于治疗COPD中粘液过量产生的治疗。