PEDF Expression and Regulation in Lung Fibrosis

PEDF 在肺纤维化中的表达和调控

• 批准号: 7686319
• 负责人: GREGORY P COSGROVE
• 金额: $ 12.5万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686319
• 关键词: Apoptosis; Biological Assay; Blood Vessels; Deposition; Development; Epithelial; Extracellular Matrix; Failure; Fibrosis; Gene Targeting; HIF1A gene; Hamman-Rich syndrome; Human; Hypoxia; Hypoxia Inducible Factor; Impaired wound healing; In Situ Hybridization; Investigation; Lung; MAP2K1 gene; MAP2K6 gene; Mediator of activation protein; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Mus; Phosphotransferases; Properdin; Proteins; Pulmonary Fibrosis; Regulation; Reporter; Research Personnel; Resolution; Response Elements; Role; SB 203580; SP600125; Scheme; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Transforming Growth Factor beta; Transforming Growth Factors; Vascular Endothelial Growth Factors; Vascular remodeling; Wound Healing; human TGFB1 protein; in vivo; lung injury; pigment epithelium-derived factor; programs; promoter; response; response to injury; transcription factor; wound

DESCRIPTION (provided by applicant): The mechanisms responsible for the progressive fibrotic response seen in idiopathic pulmonary fibrosis (IPF) are poorly understood despite intense investigation. IPF may represent a maladaptive response to injury with ineffective wound repair and resulting extensive extracellular matrix deposition. We hypothesize that abnormalities in vascular remodeling, due to an imbalance of angiogenic and angiostatic mediators, result in a failure of wound healing and progressive fibrosis. We describe enhanced expression of pigment epithelium-derived factor (PEDF), a 50 kD protein with potent angiostatic and neurotrophic activities, in IPF. We hypothesize that PEDF regulates vascular development within the lung. Our studies indicate that PEDF is a TGF-beta target gene and co-localizes with it in the PIF lung, further implicating it in the pathobiology of pulmonary fibrosis. We have identified TGF-beta1 response elements, as well as hypoxia response elements, within the murine and human PEDF promoters. By stabilizing HIF-1alpha, the transcription factor that regulates VEGF expression, we demonstrate that PEDF expression is suppressed while VEGF expression is enhanced. We propose to define the cellular origin of PEDF expression within the lung using in situ hybridization, the promoter response elements using in vivo footprinting, promoter reporter assays with selective truncation and site-directed mutagenesis, and the role in which mitogen-activated kinase activity regulates PEDF expression. Lastly, we will define the function significance of PEDF expression within murine models of lung fibrosis. Our proposed investigations will not only serve to define the regulation of an important angiostatic mediator, but also provide a better understanding as those mechanisms underlying the fibrotic response within the lung.

描述（由申请人提供）： 尽管进行了激烈的研究，但对特发性肺纤维化（IPF）的进行性纤维化反应（IPF）的机制知之甚少。 IPF可能代表对损伤的不良反应，并通过无效的伤口修复，并导致广泛的细胞外基质沉积。 我们假设由于血管生成和血管静脉介质的失衡，血管重塑的异常导致伤口愈合和进行性纤维化的衰竭。 我们描述了IPF中色素上皮衍生因子（PEDF）（PEDF）的增强表达，这是一种具有有效血管性和神经营养活性的50 kD蛋白。 我们假设PEDF调节肺内的血管发育。 我们的研究表明，PEDF是TGF-β靶基因，并在PIF肺中与其共定位，进一步牵涉到肺纤维化病理学。 我们已经确定了鼠和人类PEDF启动子内的TGF-BETA1响应元件以及缺氧反应元件。 通过稳定调节VEGF表达的转录因子HIF-1Alpha，我们证明了PEDF表达在增强VEGF表达时被抑制。 我们建议使用原位杂交在肺内定义PEDF表达的细胞来源，使用体内足迹，具有选择性截断和定点诱变的启动子记者测定器的启动子响应元件，以及遇到的作用，在其中遇到膜激活激活的激酶活性调节PEDF表达。 最后，我们将定义PEDF表达在肺纤维化模型中的功能重要性。 我们提出的调查不仅将有助于定义重要的血管抑制剂的调节，而且还提供了更好的理解，因为那些在肺内纤维化反应的机制。