Role of p53 and PAI-1 in tobacco smoke exposure induced lung injury

p53 和 PAI-1 在烟草烟雾暴露引起的肺损伤中的作用

• 批准号: 9321809
• 负责人: Sreerama Shetty
• 金额: $ 17.88万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321809
• 关键词: 3' Untranslated Regions; Address; Affect; Alpha Cell; Alveolar; Apoptosis; Area; Ataxia; Binding; Blood coagulation; Catalytic Domain; Cause of Death; Cell Death; Cell Survival; Chronic Obstructive Airway Disease; Clinical; Data; Defect; Deposition; Development; Epithelial Cells; Epithelium; Exposure to; Female; Fibrin; Fibrinolysis; Genetic Transcription; In Vitro; Injury; Intervention; Intervention Studies; Knockout Mice; Laboratories; Lead; Link; Literature; Lung; MDM2 gene; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Mus; Mutate; Nucleotides; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Peptides; Pharmacology; Phosphotransferases; Plasminogen Activator Inhibitor 1; Process; Protein Phosphatase 2A Regulatory Subunit PR53; Protein p53; Protein phosphatase; Proteins; Pulmonary Emphysema; Pulmonary Surfactant-Associated Protein C; Reporting; Resistance; Respiratory System; Respiratory tract structure; Role; Signal Transduction; Source; System; TP53 gene; Tertiary Protein Structure; Tobacco smoke; Treatment Efficacy; Tumor Suppressor Proteins; United States; Wild Type Mouse; Work; caveolin 1; environmental tobacco smoke exposure; improved; in vivo; inhibitor/antagonist; injured; innovation; lung injury; mRNA Expression; male; novel; promoter; protein expression; public health relevance; response; scaffold; virtual

 DESCRIPTION (provided by applicant): Tobacco smoke (TS) exposure damages to lung epithelium and leads to chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the United States. Our findings and those of others suggest that environmental, passive TS exposure induced lung injury involves programmed alveolar epithelial cell death and abnormal fibrin turnover. In this project, we will determine how p53, a protein causing epithelial cell death, regulates plasminogen activator inhibitor-1 (PAI-1), an inhibitor of the blood clot dissolution system, to influence the viability of the lung epithelium. Increased alveolar expression of PAI-1 results in locally suppressed fibrinolysis and promotes the extensive fibrin deposition that characterizes virtually all forms of lung injuries, including those caused by environmental TS exposure. Alveolar type II epithelial cell (ATII cell) apoptosis, mediated by the tumor suppressor protein, p53, is likewise independently linked to the pathogenesis of TS-induced lung injuries such as COPD. ATII cells are a major source of PAI-1 in the lungs and also express p53. We recently presented evidence indicating that induction of p53 in injured ATII cells up-regulates both PAI-1 mRNA and protein expression. Our recent studies indicated that exposure to environmental or passive TS is linked to a disproportionate increase in p53 and PAI-1 expression and that inhibition of either p53 or PAI-1 in ATII cells mitigates apoptosis. ATII cells of mice lacking either p53 or PAI-1 expression do not undergo TS exposure-induced apoptosis, whereas ATII cells from wild-type mice show increased p53 and PAI-1 expression and apoptosis. How these newly recognized interactions contribute to the pathogenesis of TS-induced lung injury is unclear. Our project addresses this critical gap. We will use a range of molecular and novel interventional approaches that include the use of knockout mice to address our working hypothesis, which is that p53-mediated increase in expression of PAI-1 promotes ATII cell apoptosis. This is central to the pathogenesis of TS-induced lung injury and can be reversed by caveolin-1 scaffolding peptide (CSP), offering a novel interventional approach for this form of lung injury. Our objective is to determine how CSP improves TS-induced lung injury by targeting p53-mediated PAI-1 expression and ATII cell apoptosis. Our Specific Aims are: 1) to elucidate the mechanism by which CSP modulates p53-induced PAI-1 expression and ATII cell apoptosis during TS-induced lung injury. 2) to determine how reversal of TS-induced changes in the expression of microRNA-34a and surfactant protein-C by CSP mitigates ATII cell apoptosis and lung injury. We will illuminate how p53-induced PAI-1 affects alveolar injury caused by TS exposure using murine WT, p53-/- and PAI-1-/- models. This project will advance the field by elucidating how p53-mediated induction of PAI-1 regulates ATII cell viability and modulates the outcome of lung injury. The proposed interventional studies may also define new, pharmacologically targeted approaches to improve clinical outcomes for patients with lung injuries due to environmental TS exposure.

 描述（由申请人提供）：烟草烟雾（TS）暴露会损害肺上皮并导致慢性阻塞性肺病（COPD），这是美国第四大死因。我们的研究结果和其他人的研究结果表明，环境、被动性因素。 TS 暴露引起的肺损伤涉及程序性肺泡上皮细胞死亡和异常纤维蛋白更新。在本项目中，我们将确定 p53（一种导致上皮细胞死亡的蛋白质）如何调节纤溶酶原。激活剂抑制剂-1 (PAI-1) 是一种血栓溶解系统抑制剂，可影响肺上皮的活力。PAI-1 的肺泡表达增加会导致局部纤维蛋白溶解受到抑制，并促进广泛的纤维蛋白沉积，这几乎是所有纤维蛋白的特征。各种形式的肺损伤，包括由肿瘤抑制蛋白 p53 介导的环境 TS 暴露引起的肺泡 II 型上皮细胞（ATII 细胞）凋亡，也同样独立相关。 ATII 细胞是肺部 PAI-1 的主要来源，并且也表达 p53，我们最近提供的证据表明，受损 ATII 细胞中 p53 的诱导上调了 PAI-1。 1 mRNA 和蛋白质表达 我们最近的研究表明，暴露于环境或被动 TS 与 p53 和 PAI-1 表达的过度增加有关，并且 ATII 细胞中 p53 或 PAI-1 的抑制会减轻。缺乏 p53 或 PAI-1 表达的小鼠的 ATII 细胞不会经历 TS 暴露诱导的细胞凋亡，而野生型小鼠的 ATII 细胞则显示出 p53 和 PAI-1 表达增加以及这些新认识的相互作用如何促进细胞凋亡。 TS 引起的肺损伤的发病机制尚不清楚。我们的项目解决了这一关键差距，我们将使用一系列分子和新颖的干预方法，包括使用基因敲除小鼠来解决我们的工作假设，即 p53 介导的表达增加。的PAI-1 促进 ATII 细胞凋亡，这是 TS 诱导的肺损伤发病机制的核心，并且可以通过 Caveolin-1 支架肽 (CSP) 逆转，为这种形式的肺损伤提供一种新的介入方法。确定 CSP 如何通过靶向 p53 介导的 PAI-1 表达和 ATII 细胞凋亡来改善 TS 诱导的肺损伤。我们的具体目标是：1) 阐明 CSP 调节的机制。 TS 诱导的肺损伤期间 p53 诱导的 PAI-1 表达和 ATII 细胞凋亡 2) 确定 CSP 如何逆转 TS 诱导的 microRNA-34a 和表面活性剂蛋白-C 表达变化，从而减轻 ATII 细胞凋亡和肺损伤。我们将使用小鼠 WT、p53-/- 和 PAI-1-/- 模型阐明 p53 诱导的 PAI-1 如何影响 TS 暴露引起的肺泡损伤。通过阐明 p53 介导的 PAI-1 诱导如何调节 ATII 细胞活力并调节肺损伤的结果，拟议的介入研究还可能定义新的药理学靶向方法，以改善因环境 TS 暴露而导致肺损伤的患者的临床结果。 。