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.

我的主要研究兴趣是慢性炎症性肺病，以及行为和 环境暴露在肺对病理性肺部感染的先天防御中起着妥协的作用， 损伤利用临床前小鼠模型和最先进的分子、生物化学和细胞方法， 我与在VA执业的肺病学家密切合作，进行相关的临床前研究， 可用于解决当前的临床问题。我将我的发现转化为退伍军人的健康使用一个很好的- 从我们的肺移植项目中获得的表征的人肺细胞和组织生物库。我们有一个 现有的农村/农业职业暴露退伍军人队列进行相关研究， 服务区域。目前正在进行的三个主要研究项目影响退伍军人的健康： 丙二醛-乙醛加合物与肺损伤。酒精滥用导致的易感性增加 肺炎已经被发现200多年了。因为大多数（>90%）滥用酒精的人 吸烟，我们研究了香烟和酒精的联合肺损伤作用。我们发现 肺代表了形成稳定的丙二醛-乙醛蛋白的独特环境 加合物（MAA加合物），但仅在香烟烟雾和酒精暴露相结合的条件下。这些 MAA加合物导致气道上皮细胞纤毛减慢并损害先天性病原体从肺中的清除。 表面活性蛋白D（SPD）是一种主要的肺蛋白，当肺醛浓度达到 在吸烟和酒精联合暴露期间升高，仅在肺中检测到SPD-MAA加合物， 饮酒者也吸烟，导致先天肺防御的改变。（由BX 003635资助）。退伍军人- 以COVID-19为中心的研究。SARS-CoV-2病毒的致病机制和COVID的临床结局 19在具有某些预先存在的条件和高龄的个体中要糟糕得多。有必要 退伍军人的健康，以充分确定哪些风险条件特别影响他们和他们的独特需求， 在这次和未来的病毒大流行期间加强临床预防护理。老年和酗酒是 与纤毛功能障碍有关。已记录SPD可特异性结合并中和Spike 冠状病毒蛋白。我们假设，在粘膜纤毛清除水平上改变先天性肺防御， 抗微生物表面活性剂和病毒受体功能将对易感性和发病机制产生负面影响。 SARS-CoV-2，尤其是退伍军人。我们目前正在确定SARS的不同之处- 正常气道上皮和肺巨噬细胞与收集的那些细胞之间的CoV-2感染反应 来自患有COPD、酒精使用障碍或老年的个体。确定风险的形式将 授权临床医生为退伍军人做出明智的临床预防性护理决策（由BX 005413资助）。 农业有机粉尘介导的肺损伤VISN 23涵盖了一个负责最大的区域， 农业产量在全国。与奥马哈VA医生科学家合作，我们建立了一个队列， 农业暴露退伍军人探讨有机粉尘对慢性肺炎性损伤的影响。 使用已建立的小鼠模型，我们已经确定了IL-10对粉尘所致肺修复的治疗作用， 介导的损伤。我们目前正在通过一项积极的NIOSH R 01研究确定作用机制， 中部各州农业安全与健康中心（由OH 010162资助）。随着这些创新 研究项目，我已经能够提供培训和指导，以许多本科生，研究生 奥马哈VAMC和内布拉斯加大学附属大学的学生、研究员、初级科学家和医生 医疗中心（UNMC）。我们努力研究潜在的机制，并确定目标， 肺疾病汇集了医生科学家和基础科学家在奥马哈退伍军人管理局医疗 中心和UNMC，这导致了VA资助的活体动物microCT核心设施的发展，我 是奥马哈唯一一家这样的机构。