BLR&D Research Career Scientist Award

BLR

• 批准号: 9338966
• 负责人: Todd A Wyatt
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9338966
• 关键词: Acetaldehyde; Adaptive Immune System; Address; Admission activity; Age; Agriculture; Alcohol abuse; Alcohol consumption; Alcohols; Aldehydes; Animal Model; Area; Award; Binding; Biochemical; Biological Markers; Bronchoalveolar Lavage; Caring; Chronic; Cigarette; Cilia; Clinical; Colorado; Cyclic AMP-Dependent Protein Kinases; Data; Dimerization; Dust; Environment; Environmental Exposure; Environmental Impact; Epithelial; Epithelial Cells; Extramural Activities; Funding; Grant; Health; Health Care Costs; Health Care Research; Healthcare Systems; Heavy Drinking; Hospitals; Human; Immunity; Immunoglobulin A; Impairment; Individual; Infection; Inflammation; Inflammatory; Laboratories; Life; Liquid substance; Lung; Lung diseases; Malondialdehyde; Manuscripts; Military Personnel; Molecular; Morbidity - disease rate; National Institute on Alcohol Abuse and Alcoholism; Natural Immunity; Pathogenesis; Pathologic; Peer Review; Play; Pneumonia; Population; Predisposition; Proteins; Public Health; Publishing; Pulmonary Surfactant-Associated Protein D; Pulmonary Surfactant-Associated Proteins; Recording of previous events; Regulation; Research; Research Project Grants; Resolution; Respiratory Syncytial Virus Infections; Risk; Role; Sampling; Savings; Science; Scientist; Secretory Immunoglobulin A; Seminal; Services; Smoke; Smoker; Smoking; Source; Substance abuse problem; System; TNF-alpha converting enzyme; Translating; Trauma; Veterans; Virus; Virus Diseases; Work; adduct; airway epithelium; airway inflammation; alcohol exposure; alcohol research; alcohol response; alcohol use disorder; antimicrobial; career; cigarette smoking; cigarette smoking; cohort; cost; delta protein; desensitization; dimer; disorder risk; environmental tobacco smoke exposure; experience; improved; inflammatory lung disease; interest; lung injury; macrophage; member; mortality; mouse model; neutrophil; novel; pathogen; pre-clinical; pre-clinical research; prevent; programs; protein kinase C epsilon; response; scavenger receptor; sex

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 环境暴露对肺部先天防御损害的影响 对抗病理性肺损伤。利用临床前小鼠模型和最先进的技术 分子、生化和细胞方法，我与 在 VA 从事相关临床前研究的肺科医生 用于解决当前的临床问题。下面列出的是我的 VA 总结- 资助的研究项目： 丙二醛-乙醛加合物和肺损伤。酗酒导致 200 多年来，人们就知道肺炎的易感性增加。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其三倍 肺炎。酒精调节先天性和适应性免疫系统 肺部导致感染的易感性增加并降低感染的解决率。因为 大多数 (>90%) 持有澳元的人吸烟，我们选择采取 研究联合肺损伤影响的公共卫生相关方法 香烟和酒精。在我们之前的资助周期中，我们发现肺部 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），但仅在组合的条件下 香烟烟雾和酒精暴露。这些 MAA 加合物导致气道上皮细胞 纤毛减慢并损害肺部固有病原体的清除。我们出版的和 初步数据表明表面活性剂蛋白 D (SPD) 是一种主要的肺蛋白， 当混合烟雾期间肺醛浓度升高时，会加合 和酒精暴露。使用来自 NIAAA 支持的人类样本 科罗拉多州肺醇研究联盟，我们发现MAA加合物 仅在 AUD 患者的肺灌洗巨噬细胞和液体中检测到 谁也抽烟。我们观察到吸烟者的肺功能下降 粘膜 sIgA 和气道上皮的 MAA 加合物处理可阻断转胞吞 sIgA 粘膜分泌的处理。由于这些重要且新颖的 观察结果，我们现在建议扩展我们对 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 加合物在同时饮酒和饮酒的人的肺部中独特地形成 吸烟，导致先天性肺部防御能力的改变。我们将对此进行调查 通过 3 个目标进行假设： 目标 1：MAA 内合肺 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； 目标 2：MAA-SPD 通过改变上皮细胞来阻止肺中 sIgA 粘膜分泌 二聚化 IgA 的加工；目标 3：SPD 的 MAA 内合降低其抗 微生物行动（由退伍军人事务部资助 优异奖：VA I01 BX003635； 2016-2020）。