Integrating Structive Activity, Biokinetics and Response for ENP Risk Assessment

描述（由申请人提供）：PNNL U19项目建立在纳米毒理学系统方法的现有专业知识基础上，以定量理解工程纳米材料（ENP）特性如何与生物系统相互作用，并最终驱动组织处置、生理反应和引发或促进疾病的风险。我们研究计划的主要创新之一是开发互补的体外和体外剂量学模型，通过提供跨系统外推剂量的方法，共同克服了使用体外系统进行危害排序的关键障碍。我们之所以选择关注巨噬细胞炎症和病原体清除，是因为与高剂量细胞毒性相比，我们预计巨噬细胞这些关键的、相关的生理功能的破坏会增加肺部感染的风险，在低剂量的环境相关暴露下，正如空气污染所显示的那样。我们的研究项目通过测量和模拟每个系统中纳米颗粒靶细胞或组织剂量的生物学相关测量，围绕生物组织和系统的多个层面的结果整合，是我们跨学科团队先前在纳米毒理学方面的综合研究的一项创新。为了实现我们的目标，我们提出了以下3个项目：项目1：提供机械水平的理解ENP的物理化学和结构特征如何决定巨噬细胞摄取，内部运输，炎性体信号传导和吞噬细菌清除的损害，用于基于qsar的危害排名和风险评估对选定的一系列难溶性ENP的肺和全身药代动力学进行表征和建模，并确定ENP特性和调节肺部炎症反应和肺炎易感性的遗传/表型因素，用于药代动力学建模和风险评估。项目3:开发一套完整的体外和体内纳米材料剂量学模型，并应用它们来建立基于QSAR的危害排名，基于ENP对炎症小体的影响和吞噬细菌清除的损害，人类暴露限度。这是一个多学科项目，评估生物动力学，炎症反应和体外和体内病原体清除，可以比较这些系统的剂量反应，最终，到人类流行病学进行科学的ENP风险评估。

DESCRIPTION (provided by applicant): The PNNL U19 program builds on existing expertise in systems approaches to nanotoxicology to develop a quantitative understanding of how engineered nanomaterial (ENP) properties interact with biological systems and ultimately drive tissue disposition, physiological responses, and risk of initiating or promoting disease. One of the major innovations of our research program is the development of complimentary in vitro and in vitro dosimetry models, which together overcome a key obstacle to the use of in vitro systems for hazard ranking by providing a means of extrapolating doses across systems. We have chosen to focus on macrophage inflammation and pathogen clearance because, in contrast to high dose cytotoxicity, we expect that disruption of these key, linked physiological functions of macrophages can increase risk of pulmonary infection at low, environmentally relevant exposures, as has been shown for air pollution. The organization of our research program around integration of results at multiple levels of biological organization and systems through measurement and simulation of biologically relevant measures of nanoparticle target cell or tissue dose in each system, is an innovation rising from our interdisciplinary team's prior integrative research in nanotoxicology. To meet our objectives, we propose 3 projects with the following broad objectives: Project 1: Provide a mechanistic-level understanding of how physical chemical and structural features of ENP dictate macrophage uptake, internal trafficking, inflammasome signaling and impairment of phagocytic bacterial clearance for use in QSAR-based hazard rankings and risk assessment Project 2: Characterize and model the pulmonary and systemic pharmacokinetics of a selected series of poorly soluble ENP and identify ENP properties and genetic/phenotypic factors that modulate response to pulmonary inflammation and susceptibility to pneumonia for use in pharmacokinetic modeling and risk assessment. Project 3: Develop a complete suite of in vitro and in vivo nanomaterial dosimetry models and apply them to establish QSAR based hazard rankings human exposure limits based on the effects of ENP on the inflammasome and impairment of phagocytic bacterial clearance This multidisciplinary program's assessment of biokinetics, inflammatory response and pathogen clearance in vitro and in vivo, enables comparison of dose-response across these systems, and eventually, to human epidemiology for scientifically based risk assessment of ENP.