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的拟议扩展(R01 ES015241)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，以帮助NIEHS和NTP保护人类健康。我们在环境工程和大气化学、吸入毒理学和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拥有多学科团队、设施和采样器的机构，能够创造忠实地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。拟议的伙伴关系的独特优势在于，在北卡罗来纳大学环境科学和工程系的团队成员之间，以及北卡罗来纳大学和马泰克公司调查人员之间都存在着密切的互动。这一伙伴关系将检验这样一个假设，即空气污染混合物中存在的气体和颗粒物成分患与空气污染有关的肺部疾病的风险不同，物理化学过程(例如，自然太阳光、温度、湿度等)不同。大气层中的空气对这些反应有很大影响，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老鼠单独暴露在新鲜的和光化学老化的柴油废气中，或者暴露在多种污染物的城市混合物中。此外，我们将继续开发体外现场可展开装置，以提高环境水平下的灵敏度。项目2的目的是在体外和体内对小鼠体内“真实”但模型环境的影响进行筛选。我们将测定柴油尾气和尾气PM组分在体外和体内对小鼠气管上皮细胞的影响，并比较不同背景气氛下柴油尾气在体外和体内对柴油尾气的反应。项目3将在健康和哮喘人类来源的器官型培养中进行“真实”但模型环境的影响的体外筛选。具体地说，我们将确定柴油废气和气体PM组分对体外器官型人气管上皮培养的影响，并比较不同背景环境下体外器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，因为它有能力通过提供一种工具，在基于实验室的毒性机制研究和人类流行病学研究之间架起一座桥梁，这种工具可以应用于“真实”的世界大气，并能够区分复杂污染物混合物的各种成分。

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.