Alcohol inhibits anti-oxidant and immune defenses in the lung

酒精会抑制肺部的抗氧化和免疫防御

• 批准号: 9180136
• 负责人: Bashar Samih Staitieh
• 金额: $ 19.14万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9180136
• 关键词: Acute Lung Injury; Affect; Alcohol consumption; Alcohols; Alveolar; Alveolar Macrophages; American; Animal Model; Antioxidants; Attenuated; Biological Assay; Biology; Cell Line; Cells; Cessation of life; Clinical; Clinical Trials; Data; Defense Mechanisms; Disease; Doctor of Philosophy; Effector Cell; Environment; Experimental Models; Faculty; Flow Cytometry; Functional disorder; Gene Expression; Glutathione; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Immune; Immune System Diseases; Immune System and Related Disorders; Immunity; Impairment; Individual; Infection; International; Lead; Link; Lung; Lung diseases; Maintenance; Mediating; Mediator of activation protein; Mentors; Modeling; Natural Immunity; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Pharmacology; Phenotype; Physicians; Pneumonia; Population; Postdoctoral Fellow; Publishing; Rattus; Recruitment Activity; Regulation; Research; Research Personnel; Risk; Scientist; Signal Pathway; Signal Transduction; Site; Societies; System; Training; Training Programs; Translating; United States National Institutes of Health; Vulnerable Populations; Work; alcohol effect; alcohol use disorder; base; career; career development; chronic alcohol ingestion; immune function; improved; in vivo; innate immune function; lung injury; macrophage; novel; novel strategies; pathogen; problem drinker; skills; targeted treatment; transcription factor

PROJECT SUMMARY ABSTRACT This K08 application proposes a 5-year training program to develop the career of Dr. Bashar Staitieh as he studies the mechanisms by which chronic alcohol ingestion causes oxidative stress and impairs innate immune function in the lung. His primary mentor, Dr. David Guidot, is an internationally- recognized expert in the field of alcohol and lung biology who has mentored multiple post-doctoral MD and PhD trainees including four NIH K awardees and two VA Career Development awardees. Outstanding senior investigators at Emory have been recruited to join the mentoring team that will guide Dr. Staitieh’s career development. Together they determined that alcohol depletes the alveolar space of the critical anti-oxidant glutathione, in part through its previously unrecognized inhibition of the transcription factor Nrf2, and impairs the ability of the lung to defend itself against oxidative stress. This renders individuals with alcohol use disorders at increased risk for a variety of lung-related complications including pneumonia and acute lung injury. Dr. Staitieh has identified a novel and provocative connection between Nrf2 and PU.1, another key transcription factor responsible for a wide range of innate immune functions in the alveolar macrophage. His published and new preliminary data suggest that the regulation of PU.1 by Nrf2 may have significant consequences for the phenotype and function of the ‘alcoholic alveolar macrophage’. These results led to the fundamental hypothesis underlying this project that alcohol-mediated inhibition of Nrf2 and the consequent effects on PU.1 are key mediators of innate immune dysfunction in the alveolar macrophages of individuals with alcohol use disorders. Previous work by the Emory Alcohol and Lung Biology Center has established the detrimental effects of chronic alcohol ingestion on both Nrf2 and PU.1, but the connection between these two factors and the implications of their interaction have not been yet been elucidated. This K08 project reflects a novel approach to understanding the fundamental mechanisms by which alveolar macrophage innate immune functions are impaired in individuals living with alcohol use disorders. Further, the training necessary to achieve these aims will provide Dr. Staitieh with the skills to develop into an independent physician-scientist in the important field of alcohol and lung biology. Emory is among the premier sites in the world for alcohol and lung biology research and this nurturing mentoring team has a strong track record of developing the careers of alcohol researchers. Dr. Staitieh recently joined the faculty at Emory following a productive training period with NIH T32 support and is at a critical stage of his career development. The support of a K08 will enable him to meet his goal of becoming an independent physician-scientist focused on improving the health of individuals suffering from alcohol use disorders.

项目摘要摘要 这项K08申请提案提出了一项为期5年的培训计划，以发展Bashar Staitieh博士的职业 当他研究慢性酒精摄入引起氧化应激并损害的机制时 他的主要导师David Guidot博士是国际的 - 受到多次指导后博士学位的酒精和肺生物学领域的公认专家 医学博士和博士学位的学员，包括四名NIH K获奖者和两名VA职业发展获奖者。 埃默里（Emory）的杰出高级调查员已被招募加入心理团队 指导Staitieh博士的职业发展。他们共同确定酒精会耗尽肺泡 临界抗氧化剂谷胱甘肽的空间部分是通过先前未认识到的 转录因子NRF2，并损害肺部防御氧化应激的能力。 这使患有饮酒障碍的人以各种肺有关的风险增加 并发症包括肺炎和急性肺损伤。 Staitieh博士确定了一部小说， NRF2和PU.1之间的挑衅性联系，另一个关键转录因子负责 肺泡巨噬细胞中的多种先天免疫功能。他的出版和新 初步数据表明，NRF2对PU.1的调节可能对 “酒精肺泡巨噬细胞”的表型和功能。这些结果导致了 基本假设是该项目的基础，即酒精介导的NRF2抑制和 因此对PU.1的影响是肺泡先天免疫功能障碍的关键介体 酒精使用障碍的人的巨噬细胞。埃默里酒精的先前工作 肺生物学中心已经确定了慢性酒精摄入对两种NRF2的有害影响 和pu.1，但是这两个因素之间的联系及其互动的含义有 尚未阐明。这个K08项目反映了一种新颖的方法来理解 肺泡巨噬细胞先天免疫功能受损的基本机制 患有酒精使用障碍的人。此外，实现这些目标所需的培训将 为Staitieh博士提供发展为重要的物理科学家的技能 酒精和肺部生物学领域。埃默里（Emory）是世界上饮酒和肺的首要地 生物学研究和这个养育心理团队具有开发的良好记录 酒精研究人员的职业。 Staitieh博士最近加入了Emory的教师 NIH T32支持的培训期是他职业发展的关键阶段。支持 K08的一员将使他能够实现成为一个专注于独立的身体科学家的目标 改善饮酒障碍患者的健康状况。