BLR&D Research Career Scientist Application

BLR

• 批准号: 10620250
• 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: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620250
• 关键词: Acetaldehyde; Address; Admission activity; Age; Agriculture; Alcohol abuse; Alcohol consumption; Alcohols; Aldehydes; Animal Model; Animals; Area; Award; Bacterial Infections; Behavioral; Binding; Biochemical; Biological Markers; COVID-19; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Cigarette; Cilia; Clinical; Collaborations; Collecting Cell; Core Facility; Coronavirus spike protein; Cyclic AMP-Dependent Protein Kinases; Development; Dust; Elderly; Environment; Environmental Exposure; Epithelial Cells; Exposure to; Extramural Activities; Functional disorder; Funding; Future; Grant; Health; Health Care Costs; Healthcare; Healthcare Systems; Heavy Drinking; Hospitals; Human; Impairment; Individual; Inflammation; Inflammatory; Injury; Interleukin-10; Laboratories; Life; Lung; Lung Transplantation; Lung diseases; Lung infections; Macrophage; Malondialdehyde; Manuscripts; Mediating; Medical center; Mentors; Methodology; Military Personnel; Modality; Molecular; Morbidity - disease rate; Mucociliary Clearance; Natural Immunity; Nebraska; Occupational Exposure; Outcome; Output; Pathologic; Peer Review; Physicians; Play; Pneumonia; Predisposition; Preventive care; Proteins; Pulmonary Surfactant-Associated Protein D; Recording of previous events; Regulation; Research; Research Project Grants; Respiratory Syncytial Virus Infections; Risk; Role; Rural; SARS-CoV-2 infection; SARS-CoV-2 pathogenesis; Safety; Sampling; Savings; Science; Scientist; Seminal; Services; Smoke; Smoker; Smoking; Source; Substance abuse problem; System; TNF-alpha converting enzyme; Therapeutic; Time; Tissues; Training; Translating; Universities; Veterans; Virus; Virus Diseases; Virus Receptors; Work; adduct; agricultural center; airway epithelium; airway inflammation; alcohol exposure; alcohol misuse; alcohol response; alcohol use disorder; antimicrobial; biobank; career; caregiving; cell motility; chronic inflammatory lung disease; cigarette smoke; cohort; cost; desensitization; digital; disorder risk; empowerment; experience; exposure to cigarette smoke; former smoker; graduate student; human old age (65+); improved; innovation; instrument; interest; lung injury; lung repair; microCT; military trauma; military veteran; mortality; mouse model; neutrophil; pathogen; pneumonia treatment; pre-clinical; pre-clinical research; programs; protein kinase C epsilon; receptor function; response; service member; sex; surfactant; undergraduate student; viral pandemic

My primary research interests address chronic inflammatory lung disease, and the impact that behavioral and environmental exposures play in the compromise of lung innate defense against pathologic lung infections and 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. I translate my findings to Veterans’ health using a well- characterized human lung cell and tissue biobank obtained from our lung transplant program. We have an existing cohort of Veterans with rural/agricultural occupational exposures to conduct relevant studies to our service region. There are 3 major research projects currently underway that impact veterans’ health: Malondialdehyde-acetaldehyde adducts and lung injury. Alcohol abuse causing increased susceptibility to pneumonia has been known for over 200 years. Because the majority (>90%) individuals misusing alcohol smoke cigarettes, we study the combination lung injury effects of both cigarettes and alcohol. 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. Surfactant protein D (SPD) is a major lung protein that gets adducted when lung aldehyde concentrations are elevated during combined smoke and alcohol exposure and SPD-MAA adducts are detected in the lung only in drinkers who also smoke, leading to alterations in innate lung defense. (Funded by BX003635). Veterans- centric COVID-19 research. The pathogenesis of the SARS-CoV-2 virus and clinical outcomes from COVID 19 are far worse in individuals with certain pre-existing conditions and those of advanced age. It is essential to the health of Veterans to fully define which at-risk conditions particularly impact them and their unique needs to empower clinical preventive care during this and future viral pandemics. Old age and alcohol misuse are associated with cilia dysfunction. SPD has been documented to specifically bind to and neutralize the Spike protein of coronavirus. We hypothesize that altered innate lung defense at the level of mucociliary clearance, anti-microbial surfactants, and viral receptor function will negatively impact susceptibility and pathogenesis of SARS-CoV-2, placing Veterans particularly in harm’s way. We are currently identifying differences in SARS- CoV-2 infection responses between normal airway epithelium and lung macrophages and those cells collected from individuals with COPD, with alcohol use disorder, or of old age. Defining the modalities of risk will empower clinicians to make informed clinical preventive care decisions for Veterans (Funded by BX005413). Agricultural organic dust-mediated lung injury. VISN 23 encompasses a region responsible for the largest agricultural output in the nation. In collaboration with Omaha VA physician scientists, we have built a cohort of Veterans with agricultural exposures to explore the impact of organic dusts on chronic lung inflammatory injury. Using established mouse models, we have identified the therapeutic impact of IL-10 on lung repair from dust- mediated injury. We are currently defining the mechanisms of action through an active NIOSH R01 study and the Central States Center for Agricultural safety and Health (Funded by OH010162). With these innovative research programs, I have been able to provide training and mentoring to many undergraduates, graduate students, fellows, junior scientists and physicians at the Omaha VAMC and affiliated University of Nebraska Medical Center (UNMC). Our efforts to investigate the underlying mechanisms and identify targets for pulmonary disease have brought together physician scientists and basic scientists at the Omaha VA medical center and UNMC, which has led to the development of a VA-funded live-animal microCT Core facility, which I supervise and is the only such instrument in Omaha.

我的主要研究兴趣解决了慢性炎性肺病，以及行为和行为的影响 环境暴露在针对病理肺部感染和 受伤。利用临床前小鼠模型和最先进的分子，生化和细胞方法， 我与在弗吉尼亚州实践的肺科医生紧密合作，以进行相关的临床前研究 可用于解决当前的临床问题。我将发现的发现转化为退伍军人的健康 表征了从我们的肺移植程序获得的人类肺细胞和组织生物库。我们有一个 现有的与农村/农业职业暴露的退伍军人队列，向我们进行相关研究 服务区域。目前正在进行3个主要的研究项目，影响了退伍军人的健康： 丙二醛 - 乙醛加合物和肺损伤。酗酒导致对 肺炎已有200多年了。因为大多数（> 90％）的人缺少专辑 抽烟，我们研究香烟和酒精的肺损伤作用。我们确定了这一点 肺代表了形成稳定丙二醛醛醛蛋白的独特环境 加合物（MAA加合物），但仅在香烟烟雾和酒精暴露的条件下。这些 MAA加合物导致气道上皮细胞纤毛减慢并损害肺部的先天病原体清除率。 表面活性剂蛋白D（SPD）是一种主要的肺蛋白，当肺醛浓度为 仅在肺中检测到烟气和酒精暴露和饮酒的联合升高，仅在肺中检测到 也吸烟的饮酒者，导致先天肺防御的改变。 （由BX003635资助）。退伍军人 - 以中心的共同研究研究。 SARS-COV-2病毒的发病机理和COVID的临床结果 在患有某些先前存在的条件和高龄的人的个人中，有19个差得多。至关重要 退伍军人的健康完全定义了哪些处于危险的条件，尤其影响他们的独特需求 在此期间和将来的病毒大流行期间赋予临床预防保健能力。老年和滥用酒精是 与纤毛功能障碍有关。 SPD已被记录在特异性结合和中和尖峰 冠状病毒的蛋白质。我们假设在粘膜清除水平上改变了先天肺防御， 抗微生物表面和病毒受体功能将对易感性和发病机理产生负面影响 SARS-COV-2，尤其是在伤害方面放置退伍军人。我们目前正在确定SARS的差异 - 正常气道上皮和肺巨噬细胞和收集的细胞之间的COV-2感染反应 来自患有COPD的人，饮酒障碍或老年。定义风险的方式将 授权临床医生为退伍军人做出明智的临床预防保健决定（由BX005413资助）。 农业有机粉尘介导的肺损伤。 Visn 23涵盖了负责最大的地区 全国农业产出。与奥马哈VA物理科学家合作，我们建立了一系列 有农业暴露的退伍军人探索有机粉尘对慢性肺部感染的影响。 使用已建立的小鼠模型，我们已经确定了IL-10对粉尘中肺修复的治疗影响 介导的伤害。我们目前正在通过主动的NIOSH R01研究来定义行动机制，并 中央国家农业安全与健康中心（由OH010162资助）。使用这些创新 研究计划，我能够为许多本科生提供培训和心理 奥马哈VAMC和内布拉斯加州会员大学的学生，研究员，初级科学家和医生 医疗中心（UNMC）。我们为调查潜在机制并确定目标的努力 肺部疾病已将体育科学家和基础科学家汇集在一起 中心和UNMC，这导致了VA资助的现场微型核心设施的发展，我 监督，是奥马哈唯一的这种乐器。