The impact of vaping aerosol exposure on innate pulmonary defense mechanisms in nonhuman primates

项目摘要 Vaping是一个严重的公共卫生问题，与2009年的住院和死亡事件有关。 2019.这些与电子烟相关的肺损伤（EVALI）的爆发与增加使用 青少年和年轻人使用电子烟设备。EVALI的快速发病和 巨噬细胞在其进展中的作用，支持先天免疫系统在EVALI发病机制中的作用。 尽管它的使用越来越多，但目前对vaping对肺部免疫学和生理学的影响知之甚少 强调需要动物模型来更好地了解其影响。小动物模型显示 暴露于雾化气溶胶后的病理变化;然而，它们并不能概括病理变化。 EVALI在人类中的表现需要一个更可翻译的动物模型来研究 EVALI的发病机制。非人灵长类动物（NHP）非常适合研究呼吸系统疾病， 这是由于它们在肺解剖学和免疫学方面的相似性， 动物模型在这里，我们的目标是利用NHP模型来研究电子烟气溶胶暴露对 先天性肺防御机制我们将纵向评估肺和先天免疫功能 （免疫细胞浸润，肺泡巨噬细胞吞噬作用，以及细胞因子，趋化因子和 防御分子）在每天vaping气溶胶暴露的四周内。在研究结束时， 通过严格的死后检查和上部取样， 下呼吸道这项研究产生的数据将为雾化气溶胶的机制提供信息。 影响先天性肺部防御，这是当今高度传染性呼吸道疾病时期的一个重要研究领域 疾病此外，本研究将为未来评估贡献的调查提供初步数据 电子烟液体中的单个成分（尼古丁、四氢大麻酚和维生素E乙酸酯）;以及 在共病条件（SARS-CoV-2和HIV/SIV）的背景下使用电子烟， 几个供资机构（NIDA、NHLBI、NIAID）。这项拟议的研究和指导职业发展计划 将在杜兰国家灵长类动物研究中心在罗纳德维齐博士的指导下进行 还有查德·罗伊TNPRC一直是生物医学研究的国家资源和卓越中心 使用非人类灵长类动物超过50年。TNPRC对培训和指导有着坚定的承诺 并提供支持（财政和努力），为早期阶段创造丰富多样的培训环境， investigators. TNPRC完全支持布莱尔博士的职业目标，即发展成为一个独立资助的 私人调查员与NHP模型合作，研究具有重大公共卫生意义的疾病。专用 K 01提供的时间和额外的指导将帮助布莱尔博士完善他的赠款写作和项目 管理技能，以确保他未来的R 01提案的成功。

PROJECT SUMMARY Vaping is a serious public health concern that was associated with outbreaks of hospitalizations and deaths in 2019. These outbreaks of electronic vaping associated lung injury (EVALI) coincided with increased use of electronic vaping devices by adolescents and young adults. The rapid disease onset of EVALI and the role of macrophages in its progression, support a role for the innate immune system in the pathogenesis of EVALI. Despite its rising use little is currently known about the effect of vaping on pulmonary immunology and physiology highlighting the need for animal models to better understand its effects. Small animal models have shown pathologic changes following exposure to vaping aerosols; however, they do not recapitulate the pathologic manifestations of EVALI reported in humans necessitating a more translatable animal model to investigate the pathogenesis of EVALI. Nonhuman primates (NHPs) are ideally suited for studying respiratory diseases in humans due to their similarity in both pulmonary anatomy and immunology which provide advantages over other animal models. Here, we aim to utilize a NHP model to investigate the impact of vaping aerosol exposure on innate pulmonary defense mechanisms. We will longitudinally assess pulmonary and innate immune function (immune cell infiltrates, alveolar macrophage phagocytosis, and secretion of cytokines, chemokines, and defense molecules) over a four-week period of daily vaping aerosol exposure. At the end of the study, correlation with pathologic changes will occur through rigorous postmortem examination and sampling of the upper and lower respiratory tract. The data generated from this study will inform on mechanisms by which vaping aerosols effect innate pulmonary defenses, an important area of investigation in this time of highly infectious respiratory diseases. Furthermore, this study will provide preliminary data for future investigations evaluating the contribution of individual constituents within the vaping liquid (nicotine, tetrahydrocannabinol, and vitamin E acetate); and vaping in the context of comorbid conditions (SARS-CoV-2 and HIV/SIV), areas of special interest supported by several funding agencies (NIDA, NHLBI, NIAID). This proposed study and Mentored Career Development Plan will be conducted at the Tulane National Primate Research Center under the guidance of Drs. Ronald Veazey and Chad Roy. The TNPRC has been a national resource and center of excellence for biomedical research using nonhuman primates for over 50 years. The TNPRC has a strong commitment to training and mentorship and provides support (financial and effort-based) to create a rich and diverse training environment for early-stage investigators. The TNPRC fully supports Dr. Blair in his career goal to develop into an independently funded private investigator working with NHP models to study diseases of major public health importance. The dedicated time and additional mentorship provided by this K01 will help Dr. Blair refine his grant writing and project management skills to ensure the success of his future R01 proposals.