Bioengineering partnership to improve chemical hazard testing paradigms

现有生物工程伙伴关系（R01 ES 015241）的拟议扩展是一项有效、广泛和跨学科的努力，旨在设计新的工具、方法和知识，以帮助NIEHS和NTP保护人类健康。我们招募了一支在环境工程和大气化学、吸入毒理学以及环境相关疾病的人类模型领域经验丰富的优秀科学家团队。该研究所是世界上唯一一家拥有多学科团队、设施和采样器的机构，能够创建忠实再现真实的空气的模型大气，并通过直接暴露肺细胞或动物来量化其对健康的不利影响。拟议的合作伙伴关系的独特优势是现有的密切互动，无论是在团队成员谁是在环境科学与工程系在北京大学，以及北京大学和MatTek公司的调查人员之间。这一伙伴关系将检验以下假设：空气污染混合物中存在的气体和颗粒成分与空气污染相关的肺部疾病的风险不同，物理化学过程（例如，自然阳光、温度、湿度等）大气中的二氧化碳会显著影响这些反应，遗传和潜在疾病是易感性的重要决定因素。将通过三个项目检验这一假设。项目1将为吸入毒理学研究提供环境工程解决方案。我们将使生物组织和小鼠单独暴露于新鲜和光化学老化的柴油废气中，或暴露于多污染物的城市混合物中。此外，我们将继续开发体外现场部署装置，以提高环境水平下的灵敏度。项目2的目的是进行体外和体内筛选的影响“真实的”，但在小鼠模型的气氛。我们将确定柴油机废气和气体+PM组分对体外和体内小鼠气管上皮细胞的影响，并比较柴油机废气在体外和体内小鼠不同背景气氛下的反应。项目3将进行“真实的”的影响，但在健康和哮喘的人源性器官型培养模型的气氛体外筛选。具体而言，我们将确定柴油机废气和气体+PM馏分对体外器官型人气管上皮细胞培养物的影响，并比较体外器官型人培养物在不同背景气氛下对柴油机废气的反应。将产生的数据和知识将产生影响，因为它能够提供一种工具，可应用于“真实的”世界大气，并可区分污染物复杂混合物的各种成分，从而在实验室毒性机制研究与人类流行病学研究之间架起一座桥梁。

DESCRIPTION (provided by applicant: The proposed expansion of the existing Bioengineering Partnership (R01 ES015241) is an effective, broad and interdisciplinary effort to devise novel tools, methods and knowledge that will assist the NIEHS and NTP in protecting human health. We have recruited an outstanding team of experienced scientists in the areas of environmental engineering and atmospheric chemistry, inhalational toxicology, and human models of environmentally-relevant disease. UNC is the only institution in the world that has the multidisciplinary team, facilities, and samplers capable of creating model atmospheres which faithfully reproduce real air, and quantifying their adverse health effects by directly exposing lung cells or animals. The unique advantage of the proposed partnership is existing close interaction both within the team members who are faculty at the Department of Environmental Sciences and Engineering at UNC, and between the UNC and MatTek Corporation investigators. This partnership will test the hypothesis that the risk of air pollution-related lung disease is different for gas- and particulate components present in air pollution mixtures, that physico-chemical processes (e.g., natural sun light, temperature, humidity, etc.) in the atmosphere significantly affects these responses, and that genetics and underlying disease are important determinant for susceptibility. This hypothesis will be tested through three projects. Project 1 will deliver environmental engineering solutions for inhalational toxicology research. We will expose biological tissues and mice to fresh and photochemically aged diesel exhaust alone, or in a multi-pollutant urban mix. Furthermore, we will continue development of the in vitro field-deployable device to improve sensitivity at ambient levels. Project 2 is designed to conduct in vitro and in vivo screening of the effects of "real"-but-model atmospheres in the mouse. We will determine the effects of diesel exhaust gas and gas+PM fractions on mouse tracheal epithelial cells in vitro and mice in vivo, and compare the responses of diesel exhaust in the context of different background atmospheres in vitro and in vivo in the mouse. Project 3 will conduct in vitro screening of the effects of "real"-but-model atmospheres in healthy and asthmatic human-derived organotypic cultures. Specifically, we will determine the effects of diesel exhaust gas and gas+PM fractions on organotypic human tracheal epithelial cultures in vitro, and compare the responses of in vitro organotypic human cultures to diesel exhaust in the context of different background atmospheres. The data and knowledge that will be generated will have an impact through its ability to provide a bridge between lab-based research on toxicity mechanisms and human epidemiological studies by providing a tool that can be applied to "real" world atmospheres, and can differentiate between various components of the complex mixtures of the pollutants.