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

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部疾病和 环境暴露对肺固有防御功能损害的影响 抗病理性肺损伤。利用临床前的小鼠模型和最先进的 分子、生物化学和细胞方法,我与 在退伍军人管理局执业以进行相关临床前研究的肺科医生 用于解决当前的临床问题。以下是我的退伍军人管理局的摘要- 获资助的研究项目: 丙二醛-乙醛加合物与肺损伤。酗酒导致 人们对肺炎易感性的增加已有200多年的历史。住院治疗 患有酒精使用障碍(AUD)的人因以下原因死亡的风险是前者的3倍 肺炎。酒精调节人的先天免疫系统和获得性免疫系统 肺部感染导致易感性增加,感染的消退率降低。因为 大多数(90%)患有AUDS的人吸烟,我们选择了 联合肺损伤效应研究的公共卫生学研究方法 香烟和酒都有。在我们之前的资金周期中,我们发现肺 代表了形成稳定丙二醛的独特环境- 乙醛蛋白加合物(MAA加合物),但仅在结合条件下 吸烟和酗酒。这些MAA加合物导致呼吸道上皮细胞 纤毛减慢并损害肺部固有的病原体清除。我们出版的和 初步数据表明,肺表面活性蛋白D(SPD)是一种主要的肺蛋白 在混合吸烟过程中肺醛浓度升高时被加成 以及酒精暴露。使用来自NIAAA支持的人类样本 科罗拉多州肺酒精研究联盟,我们发现MAA加合物 仅在AUDS患者的肺灌洗液、巨噬细胞和液体中检测到 也吸烟的人。我们观察到,AUD吸烟者的肺减少 黏膜SIgA和MAA加合物治疗呼吸道上皮阻断跨细胞 SIgA粘膜分泌物的加工。因为这些重要而新颖的 观察,我们现在建议扩大我们对MAA发病机制的研究 与肺巨噬细胞、粘膜SIgA和SPD的加合物。我们的总体假设是 MAA加合物在饮酒和饮酒的人的肺中以独特的形式存在 吸烟,导致先天肺防御系统的改变。我们将对此进行调查 三个目标的假设:目标1:MAA加成肺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抑制SIgA分泌 目标3:SPD的MAA加成降低其抗 微生物行动(退伍军人事务部资助)荣誉奖:VA I01 BX003635;2016-2020年)。

项目成果

期刊论文数量(0)
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会议论文数量(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:
ACORN Pilot Core
ACORN 试点核心
  • 批准号:
    10526254
  • 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:
BLR&D Research Career Scientist Application
BLR
  • 批准号:
    10620250
  • 财政年份:
    2022
  • 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:
Malondialdehyde-acetaldehyde adducts and lung injury
丙二醛-乙醛加合物与肺损伤
  • 批准号:
    9898239
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
BLR&D Research Career Scientist Award
BLR
  • 批准号:
    9898271
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
BLR&D Research Career Scientist Award
BLR
  • 批准号:
    10265367
  • 财政年份:
    2017
  • 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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