Engineering an in vitro lung model for air pollutant deposition and toxicology

描述(由申请人提供)： 候选人的总体职业目标是成为空气污染和空气污染对公众健康影响领域的领先独立研究员。与这项资助相关的职业目标是：a)增强候选人在肺部生物化学和生理学方面的知识，b)发展细胞毒理学方面的技术专长，c)开发一个将机械毒理学与空气污染物理和暴露评估领域相结合的独立研究计划。这项研究的长期目标是建立吸入空气污染物和肺部疾病之间的机械性、剂量-反应关系。合并体外毒理学和暴露评估领域是实现这一目标的必要步骤。因此，当务之急是开发一种现实的、生理的空气污染物体外沉积模型。研究人员的模型将通过近似粒子大小特定的气溶胶沉积模式来完成这一任务，这些沉积模式是保存在最先进的体外肺模型中的肺上皮细胞。该模型将根据现有最先进的模型进行开发、校准和最终验证。 体外毒理学可以作为一种相对低成本、快速的筛选方法，用于阐明多种细胞类型的这些机制。建立暴露与健康效应之间的联系1)为肺部疾病的预防和治疗提供了进一步创新的手段，特别是允许在体外筛查测试的基础上进行更有针对性的(和资源密集型的)体内实验，2)允许针对减少环境空气污染的特定有毒成分的干预和控制策略，以及3)有助于为监管机构制定更具保护性的、基于健康的标准提供必要的信息。

DESCRIPTION (provided by applicant): The candidate's overall career goal is to become a leading, independent researcher in the field of air pollution and air pollution effects on public health. Career objectives related to this grant are to: a) enhance the candidate's knowledge of pulmonary biochemistry and physiology, b) develop technical expertise in cellular toxicology, and c) develop an independent research program that integrates the fields of mechanistic toxicology with air pollution physics and exposure assessment. The long term goal of this research is to establish mechanistic, dose-response relationships between inhaled air pollutants and lung disease. Merging the fields of in vitro toxicology and exposure assessment is a necessary step in realizing this goal. Therefore, the immediate objective is to develop a realistic, physiological model for air pollutant deposition in vitro. The investigator's model will accomplish this task by approximating particle size-specific deposition patterns of particulate aerosols to pulmonary epithelial cells housed within a state-of-the-art in vitro lung model. This model will be developed, calibrated, and finally validated against the existing state-of-the-art model. In vitro toxicology can be employed as a relatively low-cost, rapid screening method for elucidating these mechanisms across many cell types. Establishing a link between exposure and health effect 1) provides a means for further innovations in the prevention and treatment of pulmonary disease, specifically allowing for more targeted (and resource-intensive) in vivo experimentation to follow from in vitro screening tests, 2) allows for intervention and control strategies targeted to reduce specific toxic components of ambient air pollution, and 3) helps provide the necessary information for regulating agencies to set more protective, health-based standards.