Functions of PPAR in the lung

PPAR 在肺中的功能

• 批准号: 6673284
• 负责人: Anton M Jetten
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6673284
• 关键词: biological signal transduction; dexamethasone; fibroblasts; gene targeting; genetic regulation; genetically modified animals; human tissue; interleukin 1; laboratory mouse; lung; microarray technology; peroxisome proliferator activated receptor; protein protein interaction; protein structure function; receptor expression; respiratory epithelium; tumor necrosis factor alpha

The objective of this study is to understand the roles that peroxisome proliferator-activated receptors (PPARs) have in the lung. We have shown that PPARb and PPARg are highly expressed in lung alveolar type II and Type I cells. We are using an in vitro cell system of murine Type II cells, specific PPAR ligands, and PPARa and PPARb knockout mice to study the function of these nuclear receptors in normal lung and during lung inflammatory disease including fibrosis and asthma. Cells were treated with PPAR-specific ligands, RNA isolated and used in microarray analysis in order to identify genes genes regulated by PPAR. These studies have identified several genes that regulated by PPARs in a time and dose-dependent manner. In addition, we are examining the interaction between cytokine and PPAR signaling. We have shown that treatment of human lung fibroblasts with interleukin 1b downregulates PPARg expression. This down-regulation is specific for IL-1b and TNF-a and is not observed with other interleukins including IL-3, IL-13, Il-8, and IL4. The decrease in PPARg expression is prevented by dexamethasone. These results suggest crosstalk between different receptor and cytokine pathways.

本研究的目的是了解过氧化物酶体增殖物激活受体 (PPAR) 在肺部的作用。我们已经证明 PPARb 和 PPARg 在 II 型和 I 型肺泡细胞中高表达。我们正在使用小鼠 II 型细胞、特定 PPAR 配体以及 PPARa 和 PPARb 敲除小鼠的体外细胞系统来研究这些核受体在正常肺部以及包括纤维化和哮喘在内的肺部炎症疾病期间的功能。用 PPAR 特异性配体处理细胞，分离 RNA 并用于微阵列分析，以鉴定受 PPAR 调节的基因。这些研究已经确定了一些受 PPAR 以时间和剂量依赖性方式调节的基因。此外，我们正在研究细胞因子和 PPAR 信号传导之间的相互作用。我们已经证明，用白细胞介素 1b 处理人肺成纤维细胞可下调 PPARg 表达。这种下调是 IL-1b 和 TNF-a 特异性的，在其他白细胞介素（包括 IL-3、IL-13、IL-8 和 IL4）中未观察到这种下调。地塞米松可以防止 PPARg 表达的降低。这些结果表明不同受体和细胞因子途径之间存在串扰。