Center for Nanobiology and Predictive Toxicology

描述（申请人提供）：纳米生物学和预测毒理学中心组建了一个多学科团队，具有纳米材料科学，毒理学，细胞生物学，高通量筛选，生物统计学，数学和计算机科学方面的专业知识，其总体目标是从根本上了解精心挑选的ENM库的物理和化学性质如何与细胞和细胞结构相互作用，包括这些在纳米-生物界面处的生物-物理化学相互作用如何可能导致肺毒性。这一目标将通过获取、合成和表征组成和组合ENM库来实现，所述ENM库集中于指定金属、金属氧化物和二氧化硅纳米颗粒（Scientific Core）的主要物理化学性质，假设其通过产生氧化应激、炎症、信号通路激活和膜溶解在肺毒性中发挥作用。这些工作将得到计算机建模的帮助，计算机建模使用热图、数学模型和机器学习来进行危险排序和风险预测。该中心的主要目标是：（i）建立一个总体预测毒理学范式，其定义为基于体外和计算机模拟方法评估ENM的体内毒性潜力（综合中心工作）;（二）建立快速通量细胞筛选并进行成像，以确定导致生物利用度和参与所讨论的损伤途径的组成和组合ENM特性（项目1）;通过在啮齿动物肺部进行滴注和吸入暴露，确定将ENM与体外损伤机制联系起来的结构-性质关系如何能够以剂量依赖方式预测肺部炎症、纤维化和细胞毒性（项目2）;（四）开发计算机毒性模型，该模型利用快速通量筛选和细胞成像数据的多变量分析来显示这些关系可用于开发概率风险排序的“纳米QSAR”（项目3）。

DESCRIPTION (provided by applicant): The Center for Nanobiology and Predictive Toxicology has assembled a multidisciplinary team with expertise in nanomaterial science, toxicology, cell biology, high throughput screening, biostatistics, mathematics and computer science with the overall goal of gaining fundamental understanding of how the physical and Chemical properties of carefully selected ENM libraries relate to interactions with cells and cellular structures, including how these bio-physicochemical interactions at the nano-bio interface may lead to pulmonary toxicity. This goal will be executed through the acquisition, synthesis and characterization of compositional and combinatorial ENM libraries that focus on the major physicochemical properties of nominated metal, metal oxide and silica nanoparticles {Scientific Core), hypothesized to play a role in pulmonary toxicity through the generation of oxidative stress, inflammation, signal pathway activation and membrane lysis. These efforts will be assisted by in silico modeling that use heatmaps, mathematical models and machine learning to perform hazard ranking and risk prediction. The major objectives of the Center are: (i) To establish an overarching predictive toxicological paradigm, which is defined as the assessment of in vivo toxic potential of ENM based on in vitro and in silico methods (integrated center effort); (ii) To establish rapid throughput cellular screening and conduct imaging to identify compositional and combinatorial ENM properties that lead to bioavailability and engagement of the injury pathways discussed above (Project 1); (iii) To establish through the performance of instillation and inhalation exposures in the rodent lung how the structure-property relationships linking ENM to in vitro injury mechanisms may be predictive of pulmonary inflammation, fibrosis and cytotoxicity in a dose-dependent fashion (Project 2); (iv) To develop in silico toxicity models that utilize multivariate analysis of the rapid throughput screening and cellular imaging data to show the relationships that can be used to develop "nano-QSARs" for probabilistic risk ranking (Project 3).