Bioengineering partnership to improve chemical hazard testing paradigms

描述（由申请人提供）：现有生物工程伙伴关系（R01 ES015241）的拟议扩展是一项有效的，广泛的和跨学科的努力，旨在设计新的工具，方法和知识，帮助NIEHS和NTP保护人类健康。我们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体模型等领域招募了一支经验丰富的杰出科学家团队。北卡罗来纳大学是世界上唯一一个拥有多学科团队、设施和采样器的机构，能够创建真实再现真实空气的模型大气，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在于，北卡罗来纳大学环境科学与工程系的团队成员以及北卡罗来纳大学和MatTek公司的研究人员之间存在着密切的互动。这一伙伴关系将检验以下假设，即空气污染混合物中存在的气体和颗粒成分与空气污染有关的肺病的风险不同，大气中的物理化学过程（例如，自然阳光、温度、湿度等）对这些反应有重大影响，遗传和潜在疾病是易感性的重要决定因素。这一假设将通过三个项目进行检验。项目1将为吸入毒理学研究提供环境工程解决方案。我们将把生物组织和小鼠单独暴露在新鲜的、光化学老化的柴油废气中，或者暴露在多重污染物的城市混合环境中。此外，我们将继续开发体外现场可部署设备，以提高环境水平的灵敏度。项目2的目的是在体外和体内筛选“真实”但模型的大气对小鼠的影响。我们将测定柴油废气和气体+PM组分对体外和体内小鼠气管上皮细胞的影响，并比较柴油废气在体外和体内不同背景大气下对小鼠的反应。项目3将在体外筛选健康和哮喘人类来源的器官型培养物中“真实”但模型的气氛的影响。具体而言，我们将确定柴油废气和气体+PM馏分对体外器官型人气管上皮培养物的影响，并比较不同背景大气下体外器官型人培养物对柴油废气的反应。将产生的数据和知识将产生影响，因为它有能力在毒性机制的实验室研究和人类流行病学研究之间架起一座桥梁，提供一种可应用于“真实”世界大气的工具，并能区分污染物复杂混合物的各种成分。

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.