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PLAGL2 Expression in Emphysema Patient Lungs

PLAGL2 在肺气肿患者肺部的表达

基本信息

批准号：
7690829
负责人：
YIH-SHENG YANG
金额：
$ 7.85万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-19 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7690829
关键词：
Alveolar wall Animal Model Antibodies Apoptosis CD8-Positive T-Lymphocytes Cells Chronic Bronchitis Chronic Obstructive Airway Disease Complementary DNA Data Development Diffuse Distal Doxycycline Endothelial Cells Epithelial Cells Female Fibrosis Formalin Frozen Sections Genes Goals Health Histologic Homeostasis Human Hypoxia Immunohistochemistry Incidence Individual Inflammation Inflammatory Investigation Lesion Lung Modeling Molecular Abnormality Molecular Profiling Mus National Heart, Lung, and Blood Institute Outcome Oxidants Pathogenesis Patients Peptide Hydrolases Phenotype Play Prevalence Probability Production Protease Inhibitor Proteins Pulmonary Emphysema Pulmonary Surfactant-Associated Protein C Relative (related person)Research Reverse Transcriptase Polymerase Chain Reaction Role Sampling Severities Severity of illness Site Staining method Stains Stress Structure of parenchyma of lung Techniques Testing Time Tissue Stains Tissues Trans-Activators Transcript Transgenes Transgenic Mice Woman Zinc Fingers abstracting adenoma airway inflammation alveolar destruction alveolar type II cell cDNA Arrays cell type cigarette smoking cytotoxic human disease in vivo laser capture microdissection macrophage mouse model neutrophil novel promoter public health relevance surfactant

项目摘要

DESCRIPTION (provided by applicant): Abstract: Pleomorphic Adenoma Gene Like-2 (PLAGL2) was identified as a transactivator of surfactant protein C (SP-C). In an attempt to examine the effect of PLAGL2 expression on SP-C production in vivo, an inducible, a lung specific PLAGL2 transgenic mouse model was developed. Lungs from transgenic mice developed an accelerated form of centrilobular emphysema following doxycycline (Dox) induction of PLAGL2 expression in type II and bronchiolar epithelial cells. This phenotype occurred in multiple mouse founders with varying PLAGL2 gene copies, indicating little contribution from integration sites or transgene copy numbers. Airway inflammation involving macrophages, neutrophils, and CD8 lymphocytes that frequently accompanies the development of COPD in humans did not appear in this PLAGL2 transgenic mouse model. Female mice displayed a higher incidence of emphysema, suggesting that this mouse model of centrilobular emphysema might mimic recent data demonstrating an increased prevalence of chronic obstructive pulmonary disease (COPD) among women. The initial characterization of this mouse model demonstrated that both PLAGL2 and SP-C expression were upregulated in distal airway epithelial cells in the induced mouse lung. The hypothesis of this study is that PLAGL2, which may play a role in surfactant protein homeostasis, is capable of initiating centrilobular emphysema in humans. This hypothesis will be tested with the supply of patient samples from LTRC. PLAGL2 expression will be examined on immunohistochemistry (IHC) staining of tissue sections from patients with histologic evidence of emphysema, COPD with predominantly chronic bronchitis, or controls. Relative levels of PLAGL2 expression will be evaluated using real-time PCR analysis of transcripts isolated from samples collected within the emphysema lesion by laser capture microdissection (LCM) technique. Scoring results obtained from both traditional IHC staining and the quantitative RT-PCR analysis of cDNA array of emphysema will be assessed to determine the correlation of PLAGL2 expression with disease severity. Given that long term lung specific expression of PLAGL2 results in centrilobular emphysema in mice, and data suggesting that PLAGL2 may either directly induce apoptosis or cause cytotoxic changes from overproduction of misprocessed SP-C, the probability that PLAGL2 plays a role in emphysema in humans with COPD is substantial. (End of Abstract) PUBLIC HEALTH RELEVANCE: Project Narrative: Using an animal model, a molecular abnormality in lung cells has been found correlated with the outcome of airspace enlargement, known as emphysema. This research will use the LTRC collected human patient samples to establish the concept of this molecule as a novel mechanism of pathogenesis of emphysema in humans.

描述（由申请人提供）：翻译后摘要：多形性腺瘤基因样蛋白2（PLAGL 2）被确定为表面活性蛋白C（SP-C）的反式激活因子。为了检测PLAGL 2表达对体内SP-C产生的影响，开发了可诱导的肺特异性PLAGL 2转基因小鼠模型。多西环素（Dox）诱导II型和细支气管上皮细胞中PLAGL 2表达后，转基因小鼠的肺发生了加速型小叶中心肺气肿。这种表型发生在具有不同PLAGL 2基因拷贝的多个小鼠建立者中，表明整合位点或转基因拷贝数的贡献很小。在这种PLAGL 2转基因小鼠模型中没有出现涉及巨噬细胞、中性粒细胞和CD 8淋巴细胞的气道炎症，这些炎症经常伴随人类COPD的发展。雌性小鼠肺气肿的发病率较高，这表明这种小叶中心肺气肿的小鼠模型可能模拟了最近的数据，表明女性慢性阻塞性肺疾病（COPD）的患病率增加。该小鼠模型的初步表征表明，PLAGL 2和SP-C表达在诱导小鼠肺的远端气道上皮细胞中上调。这项研究的假设是PLAGL 2，它可能在表面活性蛋白稳态中发挥作用，能够引发人类小叶中心肺气肿。将使用LTRC提供的患者样本对该假设进行检验。将在来自具有肺气肿、主要为慢性支气管炎的COPD的组织学证据的患者或对照的组织切片的免疫组织化学（IHC）染色上检查PLAGL 2表达。将使用激光捕获显微切割（LCM）技术对从肺气肿病变内收集的样品中分离的转录物进行实时PCR分析，评价PLAGL 2表达的相对水平。将评估从传统IHC染色和肺气肿cDNA阵列的定量RT-PCR分析获得的评分结果，以确定PLAGL 2表达与疾病严重程度的相关性。鉴于PLAGL 2的长期肺特异性表达导致小鼠的小叶中心肺气肿，并且数据表明PLAGL 2可以直接诱导细胞凋亡或由过度产生错误加工的SP-C引起细胞毒性变化，PLAGL 2在患有COPD的人的肺气肿中起作用的可能性是相当大的。 (End摘要）公共卫生相关性：项目叙述：使用动物模型，发现肺细胞中的分子异常与被称为肺气肿的空域扩大的结果相关。本研究将使用LTRC收集的人类患者样本来建立这种分子作为人类肺气肿发病机制的新机制的概念。