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

项目总结 Vaping是一个严重的公共卫生问题，与#年住院和死亡的爆发有关 2019年。这些电子蒸发相关性肺损伤(EVALI)的爆发恰逢电子蒸发相关肺损伤的使用增加 青少年和青壮年的电子蒸发设备。EVALI的快速发病及其在发病中的作用 巨噬细胞在其进展过程中，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，但目前对蒸发对肺部免疫和生理的影响知之甚少。 强调了动物模型更好地了解其影响的必要性。小动物模型已经证明 暴露于蒸发气雾剂后的病理变化；然而，它们不能概括病理变化 已报道的EVALI在人类中的表现需要更具可译性的动物模型来研究 EVALI的发病机制。非人灵长类(NHP)非常适合研究人类的呼吸道疾病 由于人类在肺部解剖和免疫学方面的相似性，这提供了比其他动物更多的优势 动物模型。在这里，我们的目标是利用NHP模型来研究汽化气溶胶暴露对 与生俱来的肺防御机制。我们将纵向评估肺部和先天免疫功能。 (免疫细胞渗入、肺泡巨噬细胞吞噬、细胞因子、趋化因子和 防御分子)进行为期四周的每日汽化气溶胶暴露。在研究结束时，相关性 会通过严格的尸检和上半身取样而发生病理变化 下呼吸道。这项研究产生的数据将为蒸发气溶胶的机制提供信息 影响先天肺防御的一个重要研究领域，在这个高度感染呼吸道的时候 疾病。此外，这项研究将为未来评估贡献的调查提供初步数据 蒸发液体中的个别成分(尼古丁、四氢大麻酚和维生素E醋酸酯)；以及 在并存条件(SARS-CoV-2和艾滋病毒/SIV)的背景下蒸发，特别感兴趣的领域由 几个资助机构(NIDA、NHLBI、NIAID)。这项建议的研究和指导职业发展计划 将在杜兰国家灵长类研究中心进行，由Ronald Veazey博士指导 还有查德·罗伊。TNPRC一直是国家生物医学研究的资源和卓越中心 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(以资金和努力为基础)，为早期阶段创造丰富多样的培训环境 调查人员。TNPRC全力支持布莱尔博士的职业目标，即发展成为一个独立资助的 与NHP模型合作研究对公共卫生具有重大意义的疾病的私家侦探。敬业的 K01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撰写和项目 管理技能，以确保他未来的R01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.