Ethanol-induced dysfunction of lung anti-microbial activity via vitamin D modulat

乙醇通过维生素 D 调节剂引起的肺抗菌活性功能障碍

• 批准号: 9324314
• 负责人: MICHAEL L MCCASKILL
• 金额: $ 14.42万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324314
• 关键词: 7-dehydrocholesterol; Academic Training; Adult Respiratory Distress Syndrome; Advisory Committees; Agriculture; Alcohol abuse; Alcohol consumption; Alveolar; American; Anatomy; Area; Attenuated; Basic Science; Behavior; Bordetella pertussis; Burn injury; Chronic; Cigarette; Cilia; Clinical; Committee Members; Contracts; DNA Adduction; Data; Development; Disease; Doctor of Philosophy; Environment; Enzymes; Epithelium; Ethanol; Faculty; Fellowship; Florida; Functional disorder; Funding; Goals; Grant; Growth; Haemophilus influenzae; Health; Hemodialysis; Human; Human body; Immune response; Immunologist; In Vitro; Incidence; Infection; Influenza; Instruction; Klebsiella pneumonia bacterium; Light; Location; Lung; Malignant neoplasm of thyroid; Manuscripts; Mediating; Medical center; Mentors; Metabolic; Metabolic Pathway; Modeling; Mycobacterium tuberculosis; National Heart, Lung, and Blood Institute; Nebraska; Occupational; Occupational Health; Outcome; Pathway interactions; Patients; Peptides; Phase; Physiological; Pigmentation physiologic function; Pneumonia; Population; Positioning Attribute; Production; Public Health; Publishing; Recording of previous events; Recovery; Research; Research Project Grants; Respiratory Tract Infections; Respiratory physiology; Rhinovirus; Risk; Role; Schools; Scientist; Series; Severities; Structure; Structure of parenchyma of lung; System; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxicology; Training; Training Programs; Translational Research; United States Dept. of Health and Human Services; United States National Institutes of Health; Universities; Virulence; Virus Diseases; Vitamin D; Work; Xenobiotics; alcohol exposure; antimicrobial; antimicrobial peptide; antimicrobial peptide LL-37; base; career development; chronic alcohol ingestion; college; experience; improved; in vivo; insight; interest; member; microbial; mortality; novel; pathogen; pressure; prevent; problem drinker; professor; respiratory health; response; sound; success; ultraviolet

DESCRIPTION (provided by applicant): My interest in human health and how the body reacts to the pressure of our environment and behaviors began in graduate school. In masters level study, I had the opportunity to participate in research projects, which gave me insight into how human body reacts negatively to certain environmental and occupational pressures. After earning my MPH, I completed a PhD from Florida A&M University in Toxicology, revealing to me the basic understanding that the small airways and alveolar spaces based on their innate function and purpose could be the anatomical equivalent of a triangle of environmental insult, innate response and human behavior. I accepted a postdoctoral research fellowship at the University of Nebraska Medical Center in October 2009, and in January 2012, I accepted an assistant professor faculty position in the UNMC College of Public Health, Department of Environmental, Agricultural and Occupational Health (EAOH). To date I have utilized my Toxicology/Public Health academic training and professional experiences to publish two additional manuscripts with my colleagues and composed a grant that was funded for one year from the Nebraska Department of Health and Human Service to investigate avenues to chemo prevent DNA adduct formation in ethanol and cigarette exposed pulmonary tissue. While preparing to become a R01-funded basic scientist, the proposed K01 support will assist in conducting more comprehensive and scientifically relevant research on the xenobiotic effects of lung antimicrobial peptide production along with resulting in a better understanding of ethanol- mediated p450 activity. I am supported by a very productive, accomplished and dedicated Advisory Committee led by Co-mentors Dr. Todd Wyatt, a leader in ethanol metabolic cilia and pulmonary dysfunction, who has been continuously NIH- and VA-funded for the last 15 years, and Dr. Jill Poole, an R01-funded clinician/scientist/immunologist currently investigating vitamin D and immune responses. My other advisory committee members are Drs. Whitney Goldner and Robert Heaney, a clinician-scientist investigating associations of vitamin D and thyroid cancer, and an extremely well published and recognized leader in the field of vitamin D translational research for decades, respectively. My goal is to be a board-certified academic toxicologist able to conduct scientifically sound, basic and translational research projects with a emphasis in pulmonary health. To accomplish this goal, I propose to A) become a Diplomat of the American Board of Toxicology; B) become competent in structuring, implementing, and analyzing translational research projects by participating in the UNMC clinical and translational training program; and C) continue professional development as a junior faculty member in the UNMC College of Public Health through scholarly training, research contributions and didactic instruction. Based on our own preliminary data and published work describing the role of ethanol in increased respiratory infection rates and severity, ARDS, and burn recovery complications, we hypothesize that ethanol decreases antimicrobial lung protection through the dysregulation of vitamin D. I will investigate this hypothesis by investigating three specific aims 1) characterize antimicrobial peptide LL-37 levels in response to both in vitro and in vivo ethanol exposure, 2) identify mechanisms by which ethanol modulates antimicrobial peptides, and 3) determine the functional consequences of ethanol on antimicrobial peptide LL-37 perturbations using an in vivo lung infection model. The NHLBI K01 would strongly boost the quality, and quantity, of my research in the area of ethanol dysmetabolism of vitamin D activation by providing protected time and allowing for further career development. (End of Abstract)

描述（由申请人提供）：我对人类健康以及身体如何对环境和行为压力做出反应的兴趣始于研究生院。在硕士阶段的学习中，我有机会参与研究项目，这让我深入了解人体如何对某些环境和职业压力产生负面反应。获得公共卫生硕士学位后，我在佛罗里达农工大学完成了毒理学博士学位，向我揭示了基本的理解，即基于其先天功能和目的的小气道和肺泡空间可能相当于环境侮辱、先天反应的三角形的解剖学等价物和人类行为。我于 2009 年 10 月接受了内布拉斯加大学医学中心的博士后研究奖学金，并于 2012 年 1 月接受了 UNMC 公共卫生学院环境、农业和职业健康系 (EAOH) 的助理教授教职。迄今为止，我已经利用我的毒理学/公共卫生学术培训和专业经验与同事一起发表了另外两篇手稿，并获得了内布拉斯加州卫生与公众服务部资助的为期一年的拨款，用于研究化疗预防 DNA 加合物的途径在暴露于乙醇和香烟的肺组织中形成。在准备成为 R01 资助的基础科学家时，拟议的 K01 支持将有助于对肺抗菌肽生产的异生素效应进行更全面和科学相关的研究，并更好地了解乙醇介导的 p450 活性。我得到了由共同导师 Todd Wyatt 博士领导的非常富有成效、卓有成就和敬业的咨询委员会的支持，他是乙醇代谢纤毛和肺功能障碍领域的领导者，在过去 15 年里一直受到 NIH 和 VA 的资助，并且Jill Poole 博士是 R01 资助的临床医生/科学家/免疫学家，目前正在研究维生素 D 和免疫反应。我的其他顾问委员会成员是博士。 Whitney Goldner 和 Robert Heaney 分别是一位研究维生素 D 与甲状腺癌关联的临床科学家，几十年来，他们分别是维生素 D 转化研究领域的一位发表了大量文章并得到公认的领导者。我的目标是成为一名经过委员会认证的学术毒理学家，能够开展科学合理的基础和转化研究项目，重点关注肺部健康。为了实现这一目标，我建议 A) 成为美国毒理学委员会的外交官； B) 通过参加 UNMC 临床和转化培训计划，成为构建、实施和分析转化研究项目的能力； C) 作为 UNMC 公共卫生学院的初级教员，通过学术培训、研究贡献和教学指导继续专业发展。根据我们自己的初步数据和已发表的描述乙醇在增加呼吸道感染率和严重程度、ARDS 和烧伤恢复并发症中的作用的工作，我们假设乙醇通过维生素 D 失调来降低抗菌肺保护作用。我将通过以下方式研究这一假设：研究三个具体目标 1) 表征抗菌肽 LL-37 水平对体外和体内乙醇的反应 暴露，2) 确定乙醇调节抗菌肽的机制，3) 使用体内肺部感染模型确定乙醇对抗菌肽 LL-37 扰动的功能影响。 NHLBI K01 通过提供受保护的时间并允许进一步的职业发展，将极大地提高我在维生素 D 激活的乙醇代谢异常领域的研究的质量和数量。 （摘要完）