Genetics of Smoke-Altered LTA4H in COPD

COPD 中烟雾改变的 LTA4H 的遗传学

基本信息

批准号：
9281903
负责人：
J Edwin Blalock
金额：
$ 39.04万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9281903
关键词：
Acrolein Affect American Aminopeptidase Anti-Inflammatory Agents Anti-inflammatory Automobile Driving Azithromycin Biological Biological Markers Catalytic Domain Cause of Death Cells Chemicals Chemotactic Factors Chronic Chronic Disease Chronic Obstructive Airway Disease Chronic lung disease Code Collagen Critical Care Disease Disease Progression Environment Enzymes Frequencies Generations Genes Genetic Genetic Polymorphism Genetic Variation Genome Genotype Glycine Heritability Human Hydrolase In Vitro Individual Inflammation Inflammatory Inflammatory Response Journals Laboratories Leukotriene A4 Leukotriene B4 Lung diseases Macrolides Measures Medicine Modeling Morbidity - disease rate Paper Pathology Pathway interactions Phenotype Play Population Predisposition Process Proline Promoter Regions Proteins Public Health Publications Regulation Reporter Risk Factors Role Science Site Smoke Smoking System Testing Time Twin Multiple Birth Variant airway inflammation base cigarette smoking cohort disorder risk enzyme activity gene environment interaction genetic analysis improved in vivo insight leukotriene A4 hydrolase mortality programs promoter public health relevance respiratory response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): A key molecule in the pathology of ongoing inflammation in COPD is the collagen fragment proline-glycine- proline (PGP). From the CCRN Macrolide trial, we found that PGP levels markedly declined in concert with azithromycin's ability to reduce COPD exacerbation frequency. To our knowledge, PGP was the only biomarker studied that showed such a profound response. More recently, our laboratory has demonstrated that PGP is negatively regulated by leukotriene A4 hydrolase (LTA4H). LTA4H is a unique enzyme which possesses both a hydrolase and aminopeptidase catalytic site. Although the hydrolase site of LTA4H is well- known to catalyze the conversion of leukotriene A4 into leukotriene B4 (a PMN chemoattractant), the substrate of the aminopeptidase activity was unknown. In a pivotal Science paper in 2010, our group demonstrated that the aminopeptidase activity degrades PGP, thereby leading to less neutrophilic (PMN) inflammation. As such, LTA4H is both pro-inflammatory (hydrolase) and anti-inflammatory (aminopeptidase) at baseline serving as a critical pivot in inflammatory responses. Cigarette smoke can upregulate the total amount of LTA4H as well as chemically modify and inactivate LTA4H's aminopeptidase but not hydrolase activity thus leaving LTB4 generation intact while allowing for chronic accumulation of inflammatory levels of PGP. Therefore, the regulation of this enzyme's amount and activities may have a crucial role in airway inflammation associated with COPD. In fact, we found marked elevation in amount but reduction in LTA4H aminopeptidase activity in smoking and COPD cohorts compared to non-lung disease cohorts although there was notable variability in each of these groups suggesting that the interaction between environment and genetics may play a key feature in COPD disease progression. In fact, previous genetic analyses have revealed a number of polymorphisms in the promoter and coding regions of LTA4H that showed associations with a variety of inflammatory disorders including COPD. In this proposal to assign alterations in LTA4H protein levels and enzyme activity to associated SNPs, we will examine genetic variation in the putative promoter region of LTA4H to determine impact on LTA4H protein levels both in vitro and in vivo. We will also explore the role of SNPs in the coding regio of LTA4H on its activity. The overall hypothesis of this proposal is that variability in expression and enzymatic activity of LTA4H impacts COPD susceptibility and related phenotypes, thus genetic variation affecting LTA4H expression and aminopeptidase function impacts COPD-related phenotypes. Such human studies are only now possible as a result of the COPDGene program, the renewal of which provides a time-sensitive window to conduct these paradigm establishing studies.

描述（由申请人提供）：慢性阻塞性肺病持续炎症病理学中的一个关键分子是胶原片段脯氨酸-甘氨酸-脯氨酸（PGP）。从 CCRN 大环内酯试验中，我们发现 PGP 水平显着下降，与阿奇霉素的能力一致。据我们所知，PGP 是唯一表现出如此显着反应的生物标志物。最近，我们的实验室证明 PGP 受到负调节。白三烯 A4 水解酶 (LTA4H) 是一种独特的酶，同时具有水解酶和氨肽酶催化位点，众所周知，LTA4H 的水解酶位点可催化白三烯 A4 转化为底物白三烯 B4。在 2010 年的一篇关键的《科学》论文中，氨肽酶的活性尚不清楚。我们的小组证明，氨肽酶活性可降解 PGP，从而减少中性粒细胞 (PMN) 炎症，因此，LTA4H 在基线时既具有促炎作用（水解酶），又具有抗炎作用（氨肽酶），是炎症反应的关键关键。香烟烟雾可以上调 LTA4H 的总量，并对 LTA4H 的氨肽酶进行化学修饰并使其失活，但不会使水解酶活性失活，从而导致 LTA4H 的活性下降。 LTB4 的生成完整，同时允许 PGP 炎症水平的长期积累，因此，该酶的量和活性的调节可能在与 COPD 相关的气道炎症中发挥至关重要的作用。事实上，我们发现 LTA4H 氨肽酶的量显着升高，但减少。与非肺部疾病队列相比，吸烟和慢性阻塞性肺病队列中的活动存在显着差异，这表明环境和遗传学之间的相互作用可能在慢性阻塞性肺病疾病进展中发挥关键作用。揭示了 LTA4H 启动子和编码区的许多多态性，这些多态性与包括 COPD 在内的多种炎症性疾病有关。在将 LTA4H 蛋白水平和酶活性的变化分配给相关 SNP 的提议中，我们将检查假定的遗传变异。 LTA4H 启动子区域以确定体外和体内 LTA4H 蛋白水平的影响我们还将探讨 LTA4H 编码区域中的 SNP 对其活性的作用。建议是表达的可变性 LTA4H 的酶活性影响 COPD 易感性和相关表型，因此影响 LTA4H 表达和氨肽酶功能的遗传变异影响 COPD 相关表型，此类人类研究只有在 COPDGene 计划的支持下才能实现，该计划的更新提供了时间。进行这些范式建立研究的敏感窗口。