Genetics of Smoke-Altered LTA4H in COPD

COPD 中烟雾改变的 LTA4H 的遗传学

• 批准号: 9502350
• 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
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9502350
• 关键词: Acrolein; Affect; American; Aminopeptidase; 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 smoke; 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

 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（由申请人证明）：COPD中炎症的病理学中的一个关键分子是胶原蛋白片段（PGP）。 Ratory证明，PGP由白细胞A4水解酶（LTA4H）定期进行，LTA4H的水解酶位点是Eukotriene B4（PMN Chemoattactant）科学论文在2010年，我们的小组证明了氨基肽酶活性降解PGP促炎（水解酶）和抗炎（氨基肽酶）在基线时作为炎症烟雾中的关键枢轴可以升级。灭活LTA4H的氨基肽酶对接水解酶ITITIOS，LTB4的生成完整，同时允许慢性炎症水平的PGP的慢性积累。 LTA4H在吸烟和同龄人群中的aminopeptitit y anthorts Althorts中的每一个都表明，在COPD疾病进展中，在发起人和遗传学中，在发起人和编码的umber sogumorphist中，THA相互作用可能起着关键作用。与多种炎症性疾病的息息相关。 lta4h的活性。 LTA4H的酶促活性影响COPD易感性和相关表型，因此，遗传变异酶的作用与COPD相关的表型的作用。

项目成果

Active transcription in the vascular bed characterizes rapid progression in idiopathic pulmonary fibrosis.

• DOI: 10.1172/jci165976
• 发表时间: 2023-08-15
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Sharma, Nirmal S;Patel, Kapil;Sari, Ezgi;Shankar, Shruti;Gastanadui, Maria G;Moncada-Giraldo, Diego;Soto-Vazquez, Yixel;Stacks, Delores;Hecker, Louise;Dsouza, Kevin;Banday, Mudassir;O'Neill, Edward;Benson, Paul;Payne, Gregory;Margaroli, Camilla;Gaggar, Amit
• 通讯作者: Gaggar, Amit