Human Lung Cell Responses to Particulate Air Pollution

描述（由申请人提供） 这一重新提交的定量研究职业发展奖的建议将为John Veranth提供资金，以联合收割机将他的燃烧和气溶胶工程背景与细胞生物化学研究相结合，由Garold Yost博士作为赞助商，Ann Aust博士作为共同赞助商。 本研究的目的是将化学工程中的传质和多相（固-液）反应分析技术应用于研究低溶解度无机空气污染颗粒与肺细胞的相互作用。 候选人的研究重点将是细胞内铁剂量的定量分析，作为可测量颗粒特性的函数，以及该剂量与细胞因子信号传导反应的相关性。将计算模拟的结果与培养细胞系、新鲜肺巨噬细胞和整个动物吸入研究中获得的实验数据进行比较。该研究的动机是生物学假设，即环境颗粒可以将不适当剂量的氧化还原活性过渡金属传递到肺组织，在那里金属催化活性氧的形成，引发细胞因子信号传导反应的级联反应。 此外，这些细胞因子信号被认为是空气污染与敏感个体某些不良反应之间的机制联系。 具体目标是：目标1：使用当前文献数据开发一种计算模型，该模型可根据可测量的颗粒特征预测靶细胞和气道组织中铁或其他过渡金属的细胞内剂量。 具体目标2：确定温度、氧化和湿度历史对无机颗粒在生理条件下释放氧化还原活性金属的能力的影响。具体目标3：通过测量细胞内铁浓度和选定的信号传导反应，阐明适当肺细胞中颗粒诱导的促炎反应的关键机制步骤的动力学。 具体目标4：使用从细胞培养和整个动物吸入研究中获得的数据来完善和改进计算模型。

DESCRIPTION (provided by applicant) This resubmitted proposal for a Mentored Quantitative Research Career Development Award will provide John Veranth with funding to combine his combustion and aerosol engineering background with cell biochemistry research under the supervision of Dr. Garold Yost as the sponsor and Dr. Ann Aust as the co-sponsor. The research is motivated by the goal of applying mass transfer and heterogeneous (solid-liquid) reaction analysis techniques from chemical engineering to the study of the interactions of low-solubility inorganic air pollution particles with lung cells. The candidate's research emphasis will be on quantitative analysis of intracellular iron dose as a function of measurable particle characteristics and the correlation of this dose with cytokine signaling responses. Results from computational simulations will be compared with experimental data obtained in cultured cell lines, in fresh lung macrophages, and from whole animal inhalation studies. The study is motivated by the biological hypothesis that ambient particles can deliver an inappropriate dose of redox active transition metals to lung tissues where the metals catalyze the formation of reactive oxygen species, initiating a cascade of cytokine signaling responses. Further, these cytokine signals are proposed as a mechanistic link between air pollution and certain adverse effects in sensitive individuals. The specific aims are: aim 1: Develop, using current literature data, a computational model that predicts the intracellular dose of iron or other transition metals in target cells and airway tissues based on measurable particle characteristics. Specific aim 2: Determine the effect of temperature, oxidation, and moisture history on the ability of inorganic particles to release redox-active metals under physiological conditions. Specific aim 3: Elucidate the kinetics of key mechanistic steps of particle-induced proinflammatory responses in appropriate lung cells by measuring intracellular iron concentration and selected signaling responses. Specific aim 4: Use data obtained from cell culture and whole animal inhalation studies to refine and improve the computational model.