BLR&D Research Career Scientist Award

BLR

• 批准号: 9898271
• 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/9898271
• 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; Consumption; Cyclic AMP-Dependent Protein Kinases; Data; Dust; Environment; Environmental Exposure; Environmental Impact; 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; Lung infections; Malondialdehyde; Manuscripts; Military Personnel; Molecular; Morbidity - disease rate; Mucous Membrane; 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; 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 smoke; cohort; cost; desensitization; dimer; disorder risk; experience; exposure to cigarette smoke; improved; inflammatory lung disease; interest; lung injury; macrophage; member; mortality; mortality risk; 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).

我的主要研究兴趣解决了慢性炎症性肺部疾病和 影响环境暴露在肺天防御的妥协中的影响 针对病理肺损伤。利用临床前的鼠标模型和最先进的 分子，生化和细胞方法，我与 在VA实践的肺科医生进行相关的临床前研究 用于解决当前的临床问题。下面列出的是我的va-摘要 资助的研究项目： 丙二醛 - 乙醛加合物和肺损伤。酗酒引起 对肺炎的敏感性提高已有200多年了。住院 患有饮酒障碍的人（AUD）有3倍死亡的风险 肺炎。酒精调节了先天性和适应性免疫系统 肺导致易感性增加和感染分辨率降低。因为 大多数人（> 90％）有auds抽烟的人，我们选择服用 研究公共卫生相关的方法是研究肺损伤的组合效应 香烟和酒精。在以前的资金周期中，我们确定了肺部 代表形成稳定的丙二醛的独特环境 乙醛蛋白加合物（MAA加合物），但仅在合并的条件下 香烟烟雾和酒精暴露。这些MAA加合物引起气道上皮细胞 纤毛减慢并损害了肺部的先天病原体清除率。我们出版的 初步数据表明，表面活性剂蛋白D（SPD）是一种主要的肺蛋白， 当烟雾混合在一起时，肺醛浓度升高时会加入 和酒精暴露。使用源自NIAAA支持的人类样品 科罗拉多肺酒精研究联盟，我们发现MAA加合物 仅在肺灌洗巨噬细胞和液体中检测到 谁也抽烟。我们已经观察到吸烟者已经减少了肺 粘膜siga和气道上皮的MAA加合物治疗transcittotic 加工Siga粘膜分泌。因为这些重要而新颖 观察结果，我们现在建议扩展有关MAA发病机理的研究 对肺巨噬细胞，粘膜Siga和SPD的加合物。我们的总体假设是 MAA加合物在食用酒精和饮用的个体的肺部独特形成 抽烟，导致先天肺防御的改变。我们将调查此事 通过3个目标假设：目标1：MAA加合的肺SPD（MAA-SPD）与肺结合 通过清道夫受体A巨噬细胞导致巨噬细胞功能的改变； AIM 2：MAA-SPD通过改变上皮细胞来防止肺中的Siga粘膜分泌 处理二聚IgA； AIM 3：SPD的MAA收益减少了其抗 微生物行动（由退伍军人事务部优异奖：VA I01资助 BX003635; 2016-2020）。