Abnormality in Gene Expression of Key Mediators of Vitamin A Action in COPD

COPD 中维生素 A 作用关键介质的基因表达异常

基本信息

批准号：
7837612
负责人：
SALIL K DAS
金额：
$ 7.33万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-11 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7837612
关键词：
Adult Age All-Trans-Retinol Binding Proteins Canis familiaris Cavia Cells Cessation of life Chronic Bronchitis Chronic Obstructive Airway Disease Cigarette Smoker Data Data Set Databases Death Rate Development Differentiation and Growth Disease Drug Delivery Systems Elastases Elements Enzymes Esterification Family Freezing Gene Expression Genes Goals Human Immunohistochemistry Individual Lung Malignant neoplasm of lung Mediator of activation protein Metabolism Microarray Analysis Mining Modeling Morbidity - disease rate Northern Blotting Nutritional status Organ Papain Patients Protein Isoforms Proteins Pulmonary Emphysema RalDH1 Rattus Reporting Research Retinoids Sampling Severities Signal Pathway Signal Transduction Signaling Molecule Smoke Smoker Specimen Staining method Stains Structure of parenchyma of lung Therapeutic Time Tissues Tretinoin United States Vitamin A Western Blotting abstracting base cigarette smoking cigarette smoking design high risk human data lung development mRNA Expression member mortality non-smoker public health relevance receptor binding repaired retinoic acid 4-hydroxylase tool

项目摘要

DESCRIPTION (provided by applicant): Chronic bronchitis and emphysema are two kinds of chronic obstructive pulmonary disease (COPD), which are important causes of morbidity and mortality in the United States. Death rates from COPD are higher among cigarette smokers and numerous findings suggest a possible association of vitamin A nutritional status with COPD and lifetime cigarette smoking. Vitamin A and its active metabolite retinoic acid (RA) are important for growth and differentiation of many tissues/organs, including lung. RA is known to be effective in promoting alveolization in papain-induced emphysema in dogs and elastase-induced emphysema in adult rats. We have reported earlier that cigarette smoke exposure in our guinea pig model caused an accumulation of retinol and a decrease in RA in lung, suggesting an abnormality in retinoid metabolism and signaling had occurred. We have recently obtained preliminary data on the protein levels and expression of some of the mediators of retinoid action of COPD lung specimens from Lung Tissue Research Consortium (LTRC). Western blot data reveal a difference in the protein levels of LRAT, CRBP-I, CRABP-II, CYP26A1, RAR1, RAR2, RAR3, and RXR1 between mild, moderate and severe emphysema. Immunohistochemical data indicate a difference on LRAT, CRBP-1, CRABP-II and RAR2 staining between these samples. Microarray data also reveal a differential expression of RDH10, RDH12, RDH13, RALDH1, RALDH2, CRABP-II, CYP26A1, RAR-1, RAR-2, RAR3, and RXR-1 between these specimens. Mining of existing GEO datasets with microarray data from human COPD studies revealed expression differences for CRBP-1 and RAR-3 with disease state. Based on the above studies, we hypothesize that in some types of COPD, there is an abnormality in the expression of genes for some of the key mediators of vitamin A action that might inhibit normal repair. The objective of this study is to establish a relationship between the severity of emphysema and levels of expression of the above referred genes as well as STRA6 (recently shown to be responsible for internalization of retinol by the cells) and RAR2 subtypes, particularly RAR22 since its expression inversely correlates with lung cancer development associated with COPD. CRBP, LRAT, STRA6, CRABP-II (human), RAR-2, and CYP26A1 are directly induced by RA. Fixed and frozen lung tissues from COPD patients with mild, moderate and severe emphysema have been obtained from LTRC for preliminary studies. For the proposed studies, specimens from the COPD patients will be age-matched and divided into two groups: smokers and non-smokers. We have developed all of the tools required for this study, including immunohistochemistry, Western blot analysis, Real-Time PCR and microarray. If successful in establishing that there is a relationship between expression of the genes of the mediators of vitamin A action and COPD, it will help us in designing potentially therapeutic drugs targeting some of these genes or in providing/restoring appropriate levels of RA. PUBLIC HEALTH RELEVANCE: The objective of this study is to elucidate the relationship between severity of emphysema in COPD patients and abnormality in the expression of key mediators of retinoid action in lung. (End of Abstract)

描述（由申请人提供）：慢性支气管炎和肺气肿是两种慢性阻塞性肺疾病（COPD），这是美国发病率和死亡率的重要原因。在吸烟者中，COPD的死亡率较高，许多发现表明维生素A营养状况与COPD和终身吸烟的可能性可能存在。维生素A及其活性代谢物视网膜酸（RA）对于包括肺在内的许多组织/器官的生长和分化很重要。众所周知，RA可有效促进帕帕因诱导的狗的肺气肿和成年大鼠弹性酶诱导的肺气肿的肺泡。我们早些时候报道说，我们的豚鼠模型中的香烟烟雾暴露导致视黄醇积聚和肺RA的降低，这表明类视黄素代谢异常和信号传导发生了异常。最近，我们获得了有关肺组织研究联盟（LTRC）的COPD肺标本的类视网膜类似作用的蛋白质水平和表达的初步数据。蛋白质印迹数据揭示了LRAT，CRBP-I，CrabP-II，CYP26A1，RAR1，RAR2，RAR3和RXR1的蛋白质水平差异。免疫组织化学数据表明这些样品之间的LRAT，CRBP-1，CRABP-II和RAR2染色有所不同。微阵列数据还揭示了RDH10，RDH12，RDH13，RALDH1，RALDH2，CRABP-II，CYP26A1，RAR-1，RAR-1，RAR-2，RAR3，RAR3和RXR-1之间的差异表达。来自人类COPD研究的微阵列数据的现有GEO数据集挖掘揭示了CRBP-1和RAR-3具有疾病状态的表达差异。基于上述研究，我们假设在某些类型的COPD中，基因表达异常，对于某些维生素的某些关键介体A的作用可能会抑制正常修复。这项研究的目的是建立肺气肿的严重程度与上述基因的表达水平与Stra6的表达水平与Stra6（最近证明是负责细胞的内在化）和RAR2亚型之间的关系，尤其是RAR22，尤其是RAR22，因为它的表达与与COPD相关的肺癌发育均与肺癌开发不相同。 RA直接诱导CRBP，LRAT，Stra6，CrabP-II（人），RAR-2和CYP26A1。从LTRC获得了来自轻度，中和重度肺气肿的COPD患者的固定和冷冻肺组织进行初步研究。对于拟议的研究，COPD患者的标本将与年龄匹配并分为两组：吸烟者和非吸烟者。我们已经开发了本研究所需的所有工具，包括免疫组织化学，Western印迹分析，实时PCR和微阵列。如果成功确定维生素A动作和COPD的基因表达之间存在关系，它将有助于我们设计针对这些基因的潜在治疗药物，或提供/恢复适当的RA水平。公共卫生相关性：这项研究的目的是阐明COPD患者中肺气肿的严重程度与肺中视网膜类似作用的关键介体表达中异常的关系。（抽象的结尾）

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Qualitative and quantitative analysis of retinol, retinyl esters, tocopherols and selected carotenoids out of various internal organs form different species by HPLC.

通过 HPLC 对不同种类的不同内脏器官中的视黄醇、视黄酯、生育酚和选定的类胡萝卜素进行定性和定量分析。

DOI：
10.1039/c0ay00288g
发表时间：
2010
期刊：
Analytical methods : advancing methods and applications
影响因子：
0
作者：
Schäffer,MichaelW;Roy,SomduttaSinha;Mukherjee,Shyamali;Nohr,Donatus;Wolter,Michael;Biesalski,HansK;Ong,DavidE;Das,SalilK
通讯作者：
Das,SalilK

Lung retinoid metabolism and signaling in chronic obstructive pulmonary disease.

慢性阻塞性肺疾病中的肺类维生素A代谢和信号传导。