BLR&D Research Career Scientist Award
BLR
基本信息
- 批准号:9338966
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcetaldehydeAdaptive Immune SystemAddressAdmission activityAgeAgricultureAlcohol abuseAlcohol consumptionAlcoholsAldehydesAnimal ModelAreaAwardBindingBiochemicalBiological MarkersBronchoalveolar LavageCaringChronicCigaretteCiliaClinicalColoradoCyclic AMP-Dependent Protein KinasesDataDimerizationDustEnvironmentEnvironmental ExposureEnvironmental ImpactEpithelialEpithelial CellsExtramural ActivitiesFundingGrantHealthHealth Care CostsHealth Care ResearchHealthcare SystemsHeavy DrinkingHospitalsHumanImmunityImmunoglobulin AImpairmentIndividualInfectionInflammationInflammatoryLaboratoriesLifeLiquid substanceLungLung diseasesMalondialdehydeManuscriptsMilitary PersonnelMolecularMorbidity - disease rateNational Institute on Alcohol Abuse and AlcoholismNatural ImmunityPathogenesisPathologicPeer ReviewPlayPneumoniaPopulationPredispositionProteinsPublic HealthPublishingPulmonary Surfactant-Associated Protein DPulmonary Surfactant-Associated ProteinsRecording of previous eventsRegulationResearchResearch Project GrantsResolutionRespiratory Syncytial Virus InfectionsRiskRoleSamplingSavingsScienceScientistSecretory Immunoglobulin ASeminalServicesSmokeSmokerSmokingSourceSubstance abuse problemSystemTNF-alpha converting enzymeTranslatingTraumaVeteransVirusVirus DiseasesWorkadductairway epitheliumairway inflammationalcohol exposurealcohol researchalcohol responsealcohol use disorderantimicrobialcareercigarette smokingcigarette smokingcohortcostdelta proteindesensitizationdimerdisorder riskenvironmental tobacco smoke exposureexperienceimprovedinflammatory lung diseaseinterestlung injurymacrophagemembermortalitymouse modelneutrophilnovelpathogenpre-clinicalpre-clinical researchpreventprogramsprotein kinase C epsilonresponsescavenger receptorsex
项目摘要
My primary research interests address chronic inflammatory lung diseases and the
impact that environmental exposures play in the compromise of lung innate defense
against pathologic lung injury. Utilizing pre-clinical mouse models and state-of-the-art
molecular, biochemical, and cellular approaches, I collaborate closely with
pulmonologists who practice at the VA to conduct relevant pre-clinical research that can
be used to address current clinical concerns. Listed below is a summary of my VA-
funded research project:
Malondialdehyde-acetaldehyde adducts and lung injury. Alcohol abuse causing
increased susceptibility to pneumonia has been known for over 200 years. Hospitalized
individuals with alcohol use disorders (AUDs) have a 3-fold risk of mortality from
pneumonia. Alcohol modulates both the innate and adaptive immune systems of the
lung resulting in increased susceptibility and decreased resolution of infection. Because
the majority (>90%) individuals with AUDs smoke cigarettes, we have chosen to take
the public health relevant approach of studying the combination lung injury effects of
both cigarettes and alcohol. In our previous funding cycle, we identified that the lungs
represent a unique environment for the formation of stable malondialdehyde-
acetaldehyde protein adducts (MAA adducts), but only under conditions of combined
cigarette smoke and alcohol exposure. These MAA adducts cause airway epithelial cell
cilia slowing and impair the innate pathogen clearance from the lung. Our published and
preliminary data demonstrate that surfactant protein D (SPD) is a major lung protein that
gets adducted when lung aldehyde concentrations are elevated during combined smoke
and alcohol exposure. Using human samples derived from the NIAAA-supported
Colorado Pulmonary Alcohol Research Consortium, we have found that MAA adducts
are detected in the lung lavage macrophages and fluid only in individuals with AUDs
who also smoke. We have observed that the AUD smokers have decreased lung
mucosal sIgA and that MAA adduct treatment of airway epithelium blocks transcytotic
processing of sIgA mucosal secretion. Because of these important and novel
observations, we now propose to extend our research on the pathogenesis of the MAA
adduct to lung macrophages, mucosal sIgA, and SPD. Our overall hypothesis is that
MAA adducts uniquely form in the lungs of individuals who consume both alcohol and
smoke cigarettes, leading to alterations in innate lung defense. We will investigate this
hypothesis through 3 aims: Aim 1: MAA adducted lung SPD (MAA-SPD) binds to lung
macrophages via scavenger receptor A leading to alterations in macrophage function;
Aim 2: MAA-SPD prevents sIgA mucosal secretion in lung by altering epithelial cell
processing of dimerized IgA; and Aim 3: MAA adduction of SPD decreases its anti-
microbial action (Funded by the Department of Veterans Affairs Merit Award: VA I01
BX003635; 2016-2020).
我的主要研究兴趣是慢性炎症性肺病和
环境暴露对肺天然防御功能影响
对抗病理性肺损伤利用临床前小鼠模型和最先进的
分子,生物化学和细胞的方法,我与
在VA执业的肺病学家进行相关的临床前研究,
用于解决当前的临床问题。下面是我的总结。
资助研究项目:
丙二醛-乙醛加合物与肺损伤。酒精滥用导致
200多年前就知道对肺炎的易感性增加。住院
酒精使用障碍(AUDs)患者的死亡风险为3倍,
肺炎酒精调节先天性和适应性免疫系统,
肺导致易感性增加和感染消退降低。因为
大多数(>90%)AUD患者吸烟,我们选择服用
联合肺损伤效应研究的公共卫生相关途径
香烟和酒精。在我们之前的资助周期中,我们发现肺
代表了形成稳定的丙二醛的独特环境-
乙醛蛋白加合物(MAA加合物),但仅在组合的条件下
吸烟和酒精暴露。这些MAA加合物导致气道上皮细胞
纤毛减慢并损害先天性病原体从肺中的清除。我们的出版和
初步数据表明表面活性蛋白D(SPD)是一种主要的肺蛋白,
当混合烟雾中肺醛浓度升高时,
和酒精暴露。使用来自NIAAA支持的
科罗拉多肺酒精研究联合会,我们发现MAA加合物
仅在AUD患者的肺灌洗液巨噬细胞和液体中检测到
他们也抽烟。我们观察到AUD吸烟者的肺功能下降,
粘膜sIgA和MAA加合物处理气道上皮阻断胞吞转运
sIgA粘膜分泌的加工。由于这些重要而新颖的
观察,我们现在建议扩大我们的研究的发病机制的MAA
肺巨噬细胞、粘膜sIgA和SPD的加合物。我们的总体假设是
MAA加合物独特地形成于既饮酒又吸烟的人的肺中。
吸烟,导致先天肺防御的改变。我们会调查的
目的1:MAA内收肺SPD(MAA-SPD)与肺结合
巨噬细胞通过清道夫受体A导致巨噬细胞功能改变;
目的2:MAA-SPD通过改变肺上皮细胞的结构,抑制sIgA的分泌,
目的3:SPD的MAA加合降低了其抗-伊加抗体的表达。
微生物作用(由退伍军人事务部资助,优异奖:VA I 01
BX 003635; 2016-2020)。
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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Todd A Wyatt其他文献
Todd A Wyatt的其他文献
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{{ truncateString('Todd A Wyatt', 18)}}的其他基金
Reactive aldehydes and alcohol misuse in lung infections
肺部感染中的活性醛和酒精滥用
- 批准号:
10581148 - 财政年份:2023
- 资助金额:
-- - 项目类别:
The Exposome and Lung Bacterial Infection: Role of Liver and Gut-derived Extracellular Vesicles
暴露体和肺部细菌感染:肝脏和肠源性细胞外囊泡的作用
- 批准号:
10526256 - 财政年份:2023
- 资助金额:
-- - 项目类别:
ShEEP Request for a Perkin Elmer Quantum GX2 Micro CT Imaging System
ShEEP 请求购买 Perkin Elmer Quantum GX2 微型 CT 成像系统
- 批准号:
9795196 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Alcohol consumption and RSV infection in airway injury
饮酒和 RSV 感染导致气道损伤
- 批准号:
8391585 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Alcohol consumption and RSV infection in airway injury
饮酒和 RSV 感染导致气道损伤
- 批准号:
8764671 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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