Project 1 Heavy Metal Induced Airway Remodeling and COPD
项目1 重金属诱导气道重塑与COPD
基本信息
- 批准号:10337087
- 负责人:
- 金额:$ 18.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-15 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalActivities of Daily LivingAddressAffectAlabamaAmidinesAreaArginineArginine deiminaseArsenicBiological MarkersCadmiumCalciumCell physiologyChronic Obstructive Pulmonary DiseaseChronic lung diseaseCitiesCitrullineCokeCommunitiesComplexCountyDataDevelopmentDimensionsDisease susceptibilityEnvironmentEnvironmental ExposureEnvironmental Risk FactorEnzymesExhalationExposure toFibroblastsFibrosisFractalsGeneticHeavy MetalsHumanIn VitroIndividualIndustrializationInhalationIntermediate Filament ProteinsLungLung diseasesManganeseMeasurementMediatingMetal exposureMusParticulate MatterPathogenesisPathway interactionsPatientsPharmacologyPhenotypePhosphorylationPlasmaPollutionPrevalenceProteinsPulmonary EmphysemaReportingRisk FactorsRoleScienceSiteSmokerSmokingSteelStructure of parenchyma of lungTLR4 geneTestingToxic Environmental SubstancesUntranslated RNAUp-RegulationValidationVimentinWorkX-Ray Computed Tomographyairway remodelingbasecigarette smokecoal-fired power plantcohortdemographicsearly detection biomarkersfine particlesinhibitormacrophagemortalitymouse modelnon-smokernovelnovel therapeutic interventionprospective testsmoking prevalencesuperfund sitetherapeutic targettool
项目摘要
The lung is a major portal for respirable environmental toxicants including heavy metals such as arsenic
(As), cadmium (Cd), and manganese (Mn), all of which are recognized to cause chronic obstructive pulmonary
disease (COPD). COPD is the third largest cause of mortality in the US. The prevalence of COPD is twice
as high in the Affected Area in Birmingham, Alabama where the Superfund site is located when compared to
the Control Area. Peptidyl arginine deiminase-2 enzyme (PAD2) in lung macrophages is activated by heavy
metals in a calcium dependent manner and induces deimination (citrullination) of vimentin to citrullinated vimentin
by the irreversible alteration of the arginine residue to the non-coded citrulline residue. Our hypothesis is that
exposure to particulate matter containing heavy metals (As, Cd and Mn) leads to induction and activation of
peptidyl arginine deiminase 2 in lung macrophages and deimination of vimentin. Activation of TLR4 in airway
fibroblasts by deiminated(citrullinated) vimentin leads to a pro-invasive, pro-fibrogenic phenotype, with
subsequent airway remodeling and COPD. We will examine this hypothesis in the following specific aims:
Aim 1: We will use a novel, selective pharmacologic inhibitor of PAD2 (AFM30a) as well as a pan PAD inhibitor
(BB-Cl-amidine) to evaluate if this leads to inhibition of citrullination of vimentin. We will also evaluate if
citrullinated vimentin modulates airway fibroblast into an invasive, phenotype in 3D lung pulmospheres through
upregulation of TLR4 in vitro. Aim 2: Determine whether heavy metal exposure leads to airway remodeling in a
murine model of COPD and is associated with the activation of PAD2, the citrullination and secretion of vimentin
and an invasive profibrotic phenotype of lung fibroblast. Pharmacologic or genetic inhibition of PAD2 will block
the development of COPD. We will use TLR4-/- mice to evaluate if citrullinated vimentin directly causes airway
remodeling and COPD as well as an invasive pro-fibrogenic phenotype of fibroblasts using 3D lung
pulmospheres. Aim 3: Determine whether PAD2 and citrullinated vimentin, present in lung macrophages, BAL,
plasma and EBC of a cohort of subjects from the Affected Area are biomarkers for COPD. Existing biospecimens
have been tested in a discovery cohort of subjects and prospective testing will be conducted in a validation cohort
of COPD subjects in parallel with airway fractal dimension (AFD) on CT scans, plasma and exhaled breath
condensate (EBC) measurements. Early biomarkers of COPD in exhaled breath condensate may help us
recognize disease susceptibility. Importantly, these studies may provide novel therapeutic strategies to
block the effects of PAD2 in patients with chronic lung disease such as COPD.
肺是可呼吸的环境有毒物质的主要门户,包括重金属,例如砷
(AS),镉(CD)和锰(MN),所有这些都被认为会引起慢性阻塞性肺
疾病(COPD)。 COPD是美国死亡率的第三大原因。 COPD的患病率是两次
在阿拉巴马州伯明翰的受影响地区高度高,与超级基金地点相比
控制区域。肺巨噬细胞中的肽基精氨酸脱氨酶-2酶(PAD2)被重量激活
金属以钙依赖性的方式,并诱导波形蛋白脱离(柠檬酸)对瓜氨酸波形蛋白
通过将精氨酸残基对非编码瓜氨酸残基的不可逆转改变。我们的假设是
暴露于含有重金属的颗粒物(AS,CD和MN)会导致诱导和激活
肺巨噬细胞中的肽基精氨酸脱氨酶2和波形蛋白的脱脂性。气道中TLR4的激活
通过能式(柠檬酸)波形蛋白的成纤维细胞导致促侵入性,促纤维化表型,并具有
随后的气道重塑和COPD。我们将在以下具体目的中检查这一假设:
AIM 1:我们将使用PAD2(AFM30A)的新型,选择性的药理学抑制剂以及PAN PAD抑制剂
(BB-CL-酰胺)评估这是否导致抑制波形蛋白的抑制作用。我们还将评估是否
瓜氨酸波形蛋白将气道成纤维细胞调节成3D肺肺泡中的侵入性表型
TLR4体外的上调。目标2:确定重金属暴露是否导致气道重塑
COPD的鼠模型,与PAD2的激活,波形蛋白的分泌有关
以及肺成纤维细胞的侵入性纤维化表型。 PAD2的药理或遗传抑制作用将阻塞
COPD的发展。我们将使用tlr4 - / - 小鼠评估柑橘类波形蛋白是否直接引起气道
使用3D肺
肺球。 AIM 3:确定PAD2和Citrulladined Vimentin是否存在于肺巨噬细胞中,BAL,
来自受影响区域的受试者队列的血浆和EBC是COPD的生物标志物。现有的生物测量
已经在受试者的发现队列中进行了测试,并将在验证队列中进行前瞻性测试
COPD受试者与CT扫描,血浆和呼气呼吸
冷凝水(EBC)测量。在呼出的呼吸凝结物中,COPD的早期生物标志物可能会帮助我们
识别疾病的敏感性。重要的是,这些研究可能会提供新颖的治疗策略
阻止PAD2对COPD等慢性肺部疾病患者的影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Veena B. Antony其他文献
Testing the Waters: Differentiating Transudates From Exudates
试水:区分渗出液和渗出液
- DOI:
10.1378/chest.108.5.1191 - 发表时间:
1995 - 期刊:
- 影响因子:9.6
- 作者:
Veena B. Antony;Kristin A. Holm - 通讯作者:
Kristin A. Holm
Cystic Fibrosis Tracheobronchial Effluent Stimulates Proliferation of Lung Fibroblasts <em>in Vitro</em>
- DOI:
10.1378/chest.95.3_supplement.234s - 发表时间:
1989-03-01 - 期刊:
- 影响因子:
- 作者:
Veda L. Ackerman;Kimberly J. Hadley;Howard Eigen;Veena B. Antony - 通讯作者:
Veena B. Antony
Veena B. Antony的其他文献
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{{ truncateString('Veena B. Antony', 18)}}的其他基金
Impact of Airborne Heavy Metals on Lung Disease and the Environment
空气中重金属对肺部疾病和环境的影响
- 批准号:
10560500 - 财政年份:2020
- 资助金额:
$ 18.39万 - 项目类别:
Impact of Airborne Heavy Metals on Lung Disease and the Environment
空气中重金属对肺部疾病和环境的影响
- 批准号:
10263534 - 财政年份:2020
- 资助金额:
$ 18.39万 - 项目类别:
Impact of Airborne Heavy Metals on Lung Disease and the Environment
空气中重金属对肺部疾病和环境的影响
- 批准号:
10337080 - 财政年份:2020
- 资助金额:
$ 18.39万 - 项目类别:
Project 1 Heavy Metal Induced Airway Remodeling and COPD
项目1 重金属诱导气道重塑与COPD
- 批准号:
10560528 - 财政年份:2020
- 资助金额:
$ 18.39万 - 项目类别:
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