Center for Nanobiology and Predictive Toxicology

描述（由申请人提供）：纳米生物学和预测毒理学中心组建了一个多学科团队，拥有纳米材料科学、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，其总体目标是获得对精心挑选的ENM文库与细胞和细胞结构相互作用的物理和化学性质的基本理解。包括这些纳米生物界面上的生物物理化学相互作用如何导致肺毒性。这一目标将通过获取、合成和表征组成和组合ENM文库来实现，这些文库侧重于指定金属、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，假设通过产生氧化应激、炎症、信号通路激活和膜裂解在肺毒性中发挥作用。这些工作将通过使用热图、数学模型和机器学习进行危害排序和风险预测的计算机建模来辅助。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方法评估ENM的体内毒性潜力（综合中心努力）；（ii）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上述损伤途径参与的组成和组合ENM特性（项目1）；（iii）通过在啮齿动物肺中进行滴注和吸入暴露，确定ENM与体外损伤机制之间的结构-性质关系如何以剂量依赖的方式预测肺部炎症、纤维化和细胞毒性（项目2）；（iv）开发利用快速通量筛选和细胞成像数据的多变量分析的硅毒性模型，以显示可用于开发用于概率风险排序的“纳米qsars”的关系（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).