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: 9119627
• 负责人: MICHAEL L MCCASKILL
• 金额: $ 14.1万
• 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/9119627
• 关键词: 7-dehydrocholesterol; Academic Training; Adult Respiratory Distress Syndrome; Advisory Committees; Agriculture; Alcohol abuse; Alcohol consumption; Alveolar; American; 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; Life; 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; Pigmentation physiologic function; Plague; Pneumonia; Population; Positioning Attribute; Production; Public Health; Publishing; Recording of previous events; Recovery; Research; Research Project Grants; Research Training; 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 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; abstracting; 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）：我对人类健康的兴趣以及身体对我们环境和行为压力的反应始于研究生院。在大师级研究中，我有机会参与研究项目，这使我深入了解了人体对某些环境和职业压力的反应。赢得了MPH后，我从佛罗里达A＆M大学获得了毒理学的博士学位，向我揭示了基本的理解，即基于它们的先天功能和目的的小气道和牙槽空间可能是对环境侮辱，先天反应和人类行为的三角形的解剖学。我于2009年10月在内布拉斯加州大学医学中心接受了博士后研究奖学金，2012年1月，我接受了环境，农业和职业健康系UNMC公共卫生学院（EAOH）的助理教授职位。迄今为止，我已经利用了我的毒理学/公共卫生学术培训和专业经验，与我的同事一起出版了另外两项手稿，并撰写了一笔赠款，该赠款由内布拉斯加州卫生和人类服务部资助了一年，以调查化学预防乙醇和香烟的肺部肺部组织中Chemo Chemo DNA加合物的途径。在准备成为R01资助的基础科学家的同时，提出的K01支持将有助于对肺抗菌肽产生的异种生物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。我得到了一个非常富有成效，成就和专门的咨询委员会的支持，该委员会由托德·怀亚特（Todd Wyatt）博士领导，托德·怀亚特（Todd Wyatt）是乙醇代谢纤毛和肺功能障碍的领导者，他在过去15年中一直在NIH-和VA资助的肺部功能障碍，以及R01资助的Imm Imm Imm Immunect和Immy Immunsist和Immy Immunist Insvistions和VA基金会。我的其他咨询委员会成员是Drs。惠特尼·戈德纳（Whitney Goldner）和罗伯特·海尼（Robert Heaney），研究维生素D和甲状腺癌的关联，几十年来，维生素D和甲状腺癌的关联分别在维生素D转化研究领域发表和公认的领导者。我的目标是成为一名经过董事会认证的学术毒理学家，能够进行科学，基本和转化的研究项目，重点是肺部健康。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）通过参与UNMC临床和转化培训计划，可以胜任结构，实施和分析翻译研究项目； c）通过学术培训，研究贡献和教学教学，继续成为UNMC公共卫生学院的初级教师的专业发展。基于我们自己的初步数据和发表的工作，描述了乙醇在增加呼吸道感染率和严重程度，ARD和燃烧恢复并发症中的作用，我们假设乙醇通过维生素的失调来降低抗菌肺的保护。体内乙醇 暴露，2）确定乙醇调节抗菌肽的机制，3）确定乙醇使用体内肺部感染模型的乙醇对抗菌肽LL-37扰动的功能后果。 NHLBI K01通过提供受保护的时间并允许进一步的职业发展，可以强烈提高我在维生素D激活乙醇二摩代谢领域的研究的质量和数量。 （抽象的结尾）