Targeting AP-1 proteins in COPD

靶向 COPD 中的 AP-1 蛋白

基本信息

批准号：
7708102
负责人：
Sekhar P. Reddy
金额：
$ 8.2万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-11 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7708102
关键词：
Address Age Air Alveolar Alveolar Cell Animal Model Apoptosis Architecture Biopsy Cell Culture Techniques Cell Proliferation Cell physiology Cells Chronic Obstructive Airway Disease Cigarette Clinical Complex Country Data Development Elastases Elastin Epithelial Cells Extracellular Matrix Extracellular Matrix Degradation FOS gene Family Family member Fibroblast Growth Factor 2 Fibroblasts Figs - dietary Gene Expression Gene Targeting Genetic Genetic Models Genetic Transcription Goals Growth Factor Heterodimerization Histopathology Homeostasis Homodimerization Human Genome Immune response Immunologics Inflammation Inflammatory Response JUN gene Leukocytes Lung Lung Inflammation Maintenance Matrix Metalloproteinases Mediating Metabolism Metalloproteinase Gene Modeling Molecular Abnormality Molecular Profiling Morbidity - disease rate Mus Pathway interactions Patients Pattern Peptide Hydrolases Phenotype Play Process Protease Inhibitor Proteins Pulmonary Emphysema Reporter Genes Reporting Repression Research Reverse Transcriptase Polymerase Chain Reaction Role Severities Severity of illness Signal Transduction Smoke Smoker Specificity Structure of parenchyma of lung Testing Therapeutic Intervention Time Tissues Transcription Factor AP-1 Type II Epithelial Receptor Cell United States Western Blotting ZIP protein abstracting bZIP Protein base biological adaptation to stress cell type cigarette smoking fos-related antigen 1 heparin-binding EGF-like growth factor inhibitor/antagonist mRNA Expression member molecular phenotype mortality mouse model non-smoker overexpression public health relevance response small molecule transcription factor

项目摘要

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is emerging as a major leading cause of morbidity and mortality in the United States and other countries. Abnormal lung cell proliferation and apoptosis, as well as extracellular matrix degradation, can alter lung cell homeostasis and architecture, leading to the development and progression of COPD. Thus, elucidating the mechanisms regulating these abnormal lung cellular processes may advance our understanding of COPD and may enable us to devise better strategies for therapeutic intervention. The human genome encodes ~ 56 b-ZIP proteins that play key roles in regulating various cellular processes, including the maintenance of tissue homeostasis. Among the most prominent and well-studied b-ZIP proteins are the Jun (c-Jun, Jun-B, and Jun-D) and Fos (c-Fos, Fos-B, Fra-1, and Fra-2) families of transcription factors. Through homo- and heterodimerization, these b-ZIP proteins form a dimeric complex known as the activator protein 1 (AP-1). AP-1 has been found to display remarkable specificity and functional importance by differentially activating gene expression. However, the expression and activation patterns of the b-ZIP proteins during the development and progression of COPD remain enigmatic. In our preliminary studies, we found that, over time, genetic disruption of the c-Jun/AP-1 transcription factor in type II epithelial cells causes enlargement of the alveolar air spaces and lung inflammation, which are cardinal features of emphysema. Interestingly, an elevated level of Fra-1 expression has been reported in the lungs of cigarette smoke-exposed mice that have developed emphysema. We have recently shown that cigarette smoke, a major determinant of COPD, strongly stimulates Fra-1 expression in lung epithelial cells. Furthermore, we have demonstrated that overexpression of Fra-1 induces matrix metalloproteinase gene expression and a fibroblastic phenotype in type II epithelial cells. Fra-1 has also been shown to regulate transrepression of the elastin gene transcription that is promoted by growth factors secreted from by extracellular matrix in response to elastase activity. These studies performed in cell culture and animal models provide compelling preliminary evidence that AP-1 signaling plays a role in COPD. Based on these data, we now postulate that dysfunctional AP-1 (c-Jun and Fra-1)-regulated gene expression contributes to the development of COPD. To test this hypothesis, we will analyze the expression and activation pattern of c-Jun and Fra-1, as well as other members of the AP-1 family, in clinical biopsies (provided by the Lung Tissue Research Consortium, LTRC) of the lungs of nonsmokers, ex-smokers, and smokers with or without progressive emphysema. The results obtained will not only allow us to correlate AP-1 signaling with COPD severity but also provide a strong rationale for further targeting Jun and Fos family members using lung-specific targeted mouse models and experimental emphysema. PUBLIC HEALTH RELEVANCE: Various cellular processes, including proliferation, differentiation, metabolism, and stress responses, are deregulated in the lungs of COPD patients. The goal of the present study is to determine whether the expression and activation patterns of the AP-1 (Jun/Fos) family of transcription factors, which regulate above cellular processes, are altered during the development and progression of COPD and whether such changes are associated with a specific cell and molecular phenotype in COPD. These studies will to further define the roles of these proteins in COPD by utilizing lung-targeted mouse models and experimental emphysema and to develop new small molecule activators/inhibitors targeting the AP-1 pathway for therapeutic intervention. (End of Abstract)

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）正在成为美国和其他国家发病和死亡的主要原因。异常的肺细胞增殖和凋亡以及细胞外基质降解可以改变肺细胞稳态和结构，导致 COPD 的发生和进展。因此，阐明调节这些异常肺细胞过程的机制可能会增进我们对慢性阻塞性肺病的理解，并使我们能够设计出更好的治疗干预策略。人类基因组编码约 56 个 b-ZIP 蛋白，这些蛋白在调节各种细胞过程（包括维持组织稳态）中发挥关键作用。最突出和研究最充分的 b-ZIP 蛋白包括 Jun（c-Jun、Jun-B 和 Jun-D）和 Fos（c-Fos、Fos-B、Fra-1 和 Fra-2）家族转录因子。通过同源二聚化和异源二聚化，这些 b-ZIP 蛋白形成二聚体复合物，称为激活蛋白 1 (AP-1)。已发现 AP-1 通过差异激活基因表达而显示出显着的特异性和功能重要性。然而，b-ZIP 蛋白在 COPD 发生和进展过程中的表达和激活模式仍然是个谜。在我们的初步研究中，我们发现，随着时间的推移，II 型上皮细胞中 c-Jun/AP-1 转录因子的基因破坏会导致肺泡气隙扩大和肺部炎症，这是肺气肿的主要特征。有趣的是，据报道，暴露于香烟烟雾并出现肺气肿的小鼠肺部中 Fra-1 表达水平升高。我们最近发现，香烟烟雾是 COPD 的主要决定因素，它会强烈刺激肺上皮细胞中 Fra-1 的表达。此外，我们还证明 Fra-1 的过度表达会诱导 II 型上皮细胞中基质金属蛋白酶基因的表达和成纤维细胞表型。 Fra-1 还被证明可以调节弹性蛋白基因转录的反式抑制，弹性蛋白基因转录的反式抑制是由细胞外基质响应弹性蛋白酶活性而分泌的生长因子促进的。这些在细胞培养和动物模型中进行的研究提供了令人信服的初步证据，表明 AP-1 信号在 COPD 中发挥作用。基于这些数据，我们现在假设功能失调的 AP-1（c-Jun 和 Fra-1）调节的基因表达有助于 COPD 的发展。为了检验这一假设，我们将分析 c-Jun 和 Fra-1 以及 AP-1 家族其他成员在临床活检（由肺组织研究联盟 (LTRC) 提供）中的表达和激活模式。非吸烟者、戒烟者和有或没有进行性肺气肿的吸烟者的肺部。获得的结果不仅使我们能够将 AP-1 信号传导与 COPD 严重程度相关联，而且还为使用肺特异性靶向小鼠模型和实验性肺气肿进一步靶向 Jun 和 Fos 家族成员提供了强有力的理由。公众健康相关性：慢性阻塞性肺病患者肺部的各种细胞过程，包括增殖、分化、代谢和应激反应，均失调。本研究的目的是确定调节上述细胞过程的转录因子 AP-1 (Jun/Fos) 家族的表达和激活模式是否在 COPD 的发生和进展过程中发生改变，以及这些变化是否与与 COPD 中的特定细胞和分子表型相关。这些研究将通过利用肺靶向小鼠模型和实验性肺气肿进一步明确这些蛋白质在慢性阻塞性肺病中的作用，并开发针对 AP-1 通路的新小分子激活剂/抑制剂进行治疗干预。（摘要完）