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

电子烟气溶胶暴露对非人灵长类动物先天肺防御机制的影响

• 批准号: 10428016
• 负责人: Robert Blair
• 金额: $ 20.05万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10428016
• 关键词: 2019-nCoV; Acute; Adolescent; Adolescent and Young Adult; Adoption; Aerosols; Affect; Alveolar; Alveolar Macrophages; Anatomy; Animal Model; Area; Autopsy; Biological Assay; Bronchiolitis; Bronchoalveolar Lavage Fluid; Cells; Centers for Disease Control and Prevention (U.S.); Centers of Research Excellence; Cessation of life; Chad; Clinical; Data; Defense Mechanisms; Defensins; Development Plans; Devices; Diffuse; Disease; Disease Outbreaks; Disease model; Dyspnea; Educational workshop; Ensure; Environment; Enzyme-Linked Immunosorbent Assay; Exposure to; Flow Cytometry; Foundations; Functional disorder; Funding; Funding Agency; Future; Goals; Grant; HIV; Hospitalization; Human; Immune; Immunohistochemistry; Immunology; Individual; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Investigation; Lipids; Liquid substance; Lower respiratory tract structure; Lung; Lung immune response; Macaca mulatta; Mentors; Mentorship; Microscopic; Modeling; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; National Institute of Drug Abuse; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Patients; Phagocytes; Phagocytosis; Phenotype; Physiology; Play; Pneumonia; Policies; Positioning Attribute; Primates; Privatization; Public Health; Pulmonary Inflammation; Pulmonary Pathology; Pulmonary function tests; Reporting; Research; Research Personnel; Resources; Respiratory Disease; Rodent Model; Role; SIV; Saline; Sampling; Study models; System; Terminal Bronchiole; Testing; Tetrahydrocannabinol; Time; Tissues; Toll-like receptors; Training; Trees; Tumor-infiltrating immune cells; United States National Institutes of Health; Vitamin E Acetate; Writing; aerosolized; airway inflammation; base; career; career development; chemokine; comorbidity; cytokine; electronic vape; improved; innate immune function; innate immune mechanisms; interest; liquid nicotine; macrophage; nonhuman primate; novel; pulmonary function; radiological imaging; receptor expression; response; skills; success; surfactant; targeted treatment; vaping; vaping associated lung injury

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.

项目概要 电子烟是一个严重的公共卫生问题，与许多国家住院和死亡的爆发有关 2019 年。这些电子烟相关肺损伤 (EVALI) 的爆发与电子烟使用的增加同时发生。 青少年和年轻人使用电子烟设备。 EVALI 的快速发病及其作用 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。 尽管电子烟的使用量不断增加，但目前人们对电子烟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 暴露于电子烟气溶胶后的病理变化；然而，它们并没有概括病理学 据报道，EVALI 在人类中的表现需要更可转化的动物模型来研究 EVALI 的发病机制。非人类灵长类动物 (NHP) 非常适合研究呼吸道疾病 人类由于其肺部解剖学和免疫学方面的相似性而比其他疾病具有优势 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）在为期四个星期的每日电子烟气溶胶暴露期间。研究结束时，相关性 通过严格的尸检和上部和上部取样，将发生病理变化 下呼吸道。这项研究产生的数据将揭示电子烟气溶胶的机制 影响先天性肺部防御，这是这个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 电子烟液体中的各个成分（尼古丁、四氢大麻酚和维生素 E 醋酸酯）；和 在合并症（SARS-CoV-2 和 HIV/SIV）的背景下使用电子烟，这是由以下机构支持的特别感兴趣的领域 多个资助机构（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进行，博士的指导下。罗纳德·维泽 和查德·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已有 50 多年的历史。 TNPRC 坚定致力于培训和指导 并提供支持（资金和精力），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 Blair 博士发展成为独立资助的 私人调查员使用 NHP 模型研究具有重大公共卫生重要性的疾病。专注的 K01 提供的时间和额外指导将帮助 Blair 博士完善他的资助写作和项目 管理技能，以确保他未来的 R01 提案取得成功。