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）暴露会损害肺上皮细胞，并导致慢性阻塞性肺病（COPD），这是美国第四大死亡原因。我们的研究结果和其他人的研究结果表明，环境，被动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周转。在这个项目中，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物抑制剂-1（派-1），一种血凝块溶解系统的抑制剂，以影响肺上皮细胞的活力。派-1的肺泡表达增加导致局部抑制的纤维蛋白溶解，并促进广泛的纤维蛋白沉积，其特征在于几乎所有形式的肺损伤，包括由环境TS暴露引起的肺损伤。由肿瘤抑制蛋白p53介导的肺泡II型上皮细胞（ATII细胞）凋亡同样独立地与TS诱导的肺损伤（如COPD）的发病机制相关。ATII细胞是肺中派-1的主要来源，也表达p53。我们最近提出的证据表明，在损伤的ATII细胞中诱导p53上调派-1 mRNA和蛋白表达。我们最近的研究表明，暴露于环境或被动TS与p53和派-1表达的不成比例增加有关，并且抑制ATII细胞中的p53或派-1可减轻凋亡。缺乏p53或派-1表达的小鼠的ATII细胞不经历TS凋亡诱导的细胞凋亡，而来自野生型小鼠的ATII细胞显示增加的p53和派-1表达和细胞凋亡。这些新认识的相互作用如何促进TS诱导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介导的派-1表达增加促进ATII细胞凋亡。这是TS诱导的肺损伤的发病机制的核心，并且可以通过小窝蛋白-1支架肽（CSP）逆转，为这种形式的肺损伤提供了一种新的干预方法。我们的目的是确定CSP如何通过靶向p53介导的派-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）探讨CSP在TS诱导肺损伤过程中调节p53诱导的派-1表达和ATII细胞凋亡的机制。2)确定CSP如何逆转TS诱导的microRNA-34 a和表面活性蛋白-C表达的变化减轻ATII细胞凋亡和肺损伤。我们将阐明p53诱导的派-1如何影响肺泡损伤所造成的TS曝光使用小鼠WT，p53-/-和派-1-/-模型。该项目将通过阐明p53介导的派-1诱导如何调节ATII细胞活力和调节肺损伤的结果来推进该领域。拟议的干预性研究还可能定义新的、有针对性的方法，以改善因环境TS暴露而导致肺损伤的患者的临床结局。