Integrating Structive Activity, Biokinetics and Response for ENP Risk Assessment

整合结构活动、生物动力学和反应进行 ENP 风险评估

• 批准号: 8017710
• 负责人: Joel G Pounds
• 金额: $ 126.4万
• 依托单位: BATTELLE PACIFIC NORTHWEST LABORATORIES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-28 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8017710
• 关键词: Integrating; Structive; Activity; Biokinetics; Response

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.

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，以发展对工程纳米材料(ENP)特性如何与生物系统相互作用并最终驱动组织处置、生理反应以及引发或促进疾病的风险的量化理解。我们研究计划的主要创新之一是开发免费的体外和体外剂量测定模型，这些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险排名的关键障碍。我们选择把重点放在巨噬细胞炎症和病原体清除上，因为与高剂量的细胞毒性相反，我们预计巨噬细胞这些关键的相关生理功能的破坏会在与环境相关的低暴露下增加肺部感染的风险，就像空气污染所显示的那样。我们的研究计划围绕着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相关测量来整合多个生物组织和系统的结果来组织，这是我们跨学科团队先前在纳米毒理学方面进行的综合研究的创新。为了达到我们的目标，我们提出了3个具有以下广泛目标的项目：项目1：提供对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、炎症体信号和吞噬细胞细菌清除障碍的机械水平的了解，以用于基于QSAR的风险排名和风险评估项目2：描述和建模一系列选定的难溶ENP的肺和全身药代动力学，并确定调节对肺部炎症和肺炎易感性的反应的ENP属性和遗传/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，并将它们用于根据ENP对炎症体和吞噬细胞细菌清除障碍的影响，建立基于QSAR的人类暴露限值。该多学科计划对体外和体内的生物动力学、炎症反应和病原体清除进行评估，能够比较这些系统的剂量-反应，并最终与人类流行病学进行比较，以进行基于科学的ENP风险评估。