Investigating Health Effects From Exposure to Organic Carbon and Nickel Aerosol

这项工作建立在申请人K99阶段之前的培训基础上，该培训旨在确定 气溶胶的化学成分最有可能对观察到的人类健康影响负责。这项工作 通过探索心血管健康的机制原因，满足了所提出的具体目标的需要 在敏感动物模型中暴露于老化或新鲜有机碳气溶胶期间观察到的影响， 研究燃烧产生的富镍颗粒在动物模型中对心肺损伤的作用。 这些目标符合国家卫生研究院更广泛的使命，即确定与下列因素相关的生物学效应： 环境污染物。 这项研究涉及一系列体内吸入暴露研究，使用小鼠模型的心血管疾病， 疾病在这个项目的过程中，6组ApoE基因敲除小鼠将暴露于各种各样的 燃烧排放气溶胶。稀释的柴油废气将用于模拟环境相关的 暴露在忙碌的道路附近。该项目还包括引进一个定制的光化学 老化室化学改性气溶胶以模拟环境气溶胶处理。这提高 通过改善接触的环境相关性， 暴露是新排放物与较老排放物的组合。在暴露之前，每个 小鼠将通过外科手术植入无线电遥测装置用于小鼠活动的真实的时间测量， 体温和双通道心电图每个暴露实验预计将发生5 每周6次，每天6小时，共20天。在暴露完成时，许多生物标志物 将测量终点。收集支气管灌洗液并离心，将上清液 分析肺损伤的生化指标（总蛋白和LDH）和炎性细胞因子。

This work builds upon previous training during the applicant's K99 phase that seeks to identify the specific chemical components of aerosol most likely responsible for observed health effects in humans. This work meets the needs ofthe proposed specific aims by exploring the mechanistic causes cardiovascular health effects observed during exposure to aged or fresh organic carbon aerosol in sensitive animal models and by investigating the role of combustion generated Ni-rich particles on cardiopulmonary injury in animal models. These aims fit within the broader mission of NIH by identifying biological effects associated with environmental contaminants. This research involves a series of in-vivo inhalation exposure studies using a murine model of cardiovascular disease. Over the course of this project, 6 sets of ApoE knockout mice will be exposed to a variety of combustion emissions aerosol. Diluted diesel exhaust will be used to mimic environmentally-relevant exposures near busy roadways. This project also includes the introduction of a custom-built photochemical aging chamber to chemically modify aerosol in order to simulate ambient aerosol processing. This improves the inhalation exposure paradigm by improving the environmental relevance of the exposure since most exposures are a composite of fresh emissions with those that are more aged. Prior to exposure, each mouse will be surgically implanted with radio telemetry devices for real time measurement of mouse activity, body temperature, and 2-channel electrocardiogram. Each exposure experiment is expected to occur 5 times per week, 6 hours per day, for 20 days. At the completion of the exposure, a number of biomarker endpoints will be measured. Brionchial lavage fluid will be collected and centrifuged and the supernatant will be analyzed for biochemical indicators of lung injury (total protein and LDH) and inflammatory cytokines.