Targeting AP-1 proteins in COPD

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率和死亡率的主要主要原因。异常的肺细胞增殖和凋亡，以及细胞外基质降解，可以改变肺细胞的稳态和结构，导致COPD的发展和进展。因此，阐明调节这些异常肺细胞过程的机制可能会促进我们对COPD的理解，并使我们能够设计更好的治疗干预策略。人类基因组编码约56种b-ZIP蛋白，这些蛋白在调节各种细胞过程中发挥关键作用，包括维持组织稳态。其中最突出和研究最充分的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化，这些b-ZIP蛋白形成称为激活蛋白1（AP-1）的二聚体复合物。已经发现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，在COPD的发展和进展过程中，b-ZIP蛋白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，在暴露于香烟烟雾的小鼠的肺中，已经报道了Fra-1表达水平的升高，这些小鼠已经发展成肺气肿。我们最近发现，吸烟，COPD的主要决定因素，强烈刺激肺上皮细胞中的Fra-1表达。此外，我们已经证明，过度表达的Fra-1诱导基质金属蛋白酶基因的表达和成纤维细胞表型的II型上皮细胞。Fra-1还显示调节弹性蛋白基因转录的反式阻遏，该转录由响应弹性蛋白酶活性的细胞外基质分泌的生长因子促进。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中起作用。基于这些数据，我们现在假设功能失调的AP-1（c-Jun和Fra-1）调节基因表达有助于COPD的发展。为了验证这一假设，我们将分析c-Jun和Fra-1以及AP-1家族其他成员在非吸烟者、戒烟者和吸烟者（有或无进行性肺气肿）肺的临床活检（由肺组织研究联盟（Lung Tissue Research Consortium，LTRC）提供）中的表达和激活模式。获得的结果不仅使我们能够将AP-1信号与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论基础。 公共卫生相关性：在COPD患者的肺中，各种细胞过程（包括增殖、分化、代谢和应激反应）被解除调节。本研究的目的是确定AP-1（Jun/Fos）家族转录因子的表达和激活模式是否在COPD的发展和进展过程中发生改变，以及这种变化是否与COPD中特定的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确定这些蛋白在COPD中的作用，并开发新的靶向AP-1通路的小分子激活剂/抑制剂用于治疗干预。 (End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)