Targeting AP-1 proteins in COPD

描述(由申请人提供)： 在美国和其他国家，慢性阻塞性肺疾病(COPD)正逐渐成为发病率和死亡率的主要原因。肺细胞的异常增殖和凋亡以及细胞外基质的降解可改变肺细胞的动态平衡和构筑，导致COPD的发生发展。因此，阐明这些异常的肺细胞过程的调节机制可能会促进我们对COPD的理解，并可能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56b-ZIP蛋白，这些蛋白在调节各种细胞过程中发挥关键作用，包括维持组织的动态平衡。其中最重要和研究最充分的b-ZIP蛋白是Jun(c-Jun、Jun-B和Jun-D)和Fos(c-Fos、Fos-B、Fra-1和Fra-2)转录因子家族。通过同源和异源二聚，这些b-ZIP蛋白形成一个二聚体复合体，称为激活蛋白1(AP-1)。AP-1通过差异激活基因表达而显示出显著的特异性和功能重要性。然而，b-ZIP蛋白在COPD发生发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转录因子的遗传破坏会导致肺泡腔扩大和肺部炎症，这是肺气肿的主要特征。有趣的是，据报道，在香烟烟雾暴露的患肺气肿的小鼠的肺部，Fra-1的表达水平升高。我们最近发现，吸烟是COPD的一个主要决定因素，它强烈刺激肺上皮细胞Fra-1的表达。此外，我们还证明了FrA-1的过表达诱导了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的表型。FRA-1还被证明调节弹性蛋白基因转录的反式抑制，弹性蛋白基因转录是由细胞外基质分泌的生长因子促进的，以响应弹性蛋白酶的活性。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)调控的基因表达在COPD的发生发展中起作用。为了验证这一假设，我们将分析c-jun和Fra-1以及AP-1家族的其他成员在非吸烟者、前吸烟者和患有或不患有进行性肺气肿的吸烟者的临床活检(由肺组织研究联盟提供)中的表达和激活模式。所获得的结果不仅使我们能够将AP-1信号与COPD的严重程度联系起来，而且也为利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论基础。公共卫生相关性：COPD患者肺部的各种细胞过程，包括增殖、分化、新陈代谢和应激反应，都被解除了调控。本研究的目的是确定调节上述细胞过程的AP-1(Jun/Fos)家族转录因子的表达和激活模式在COPD的发生发展过程中是否发生改变，以及这种变化是否与COPD的特定细胞和分子表型有关。这些研究将通过利用肺靶向小鼠模型和实验性肺气肿来进一步确定这些蛋白在COPD中的作用，并开发针对AP-1途径的新的小分子激活剂/抑制剂用于治疗干预。(摘要结束)

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)