Center for Nanobiology and Predictive Toxicology

纳米生物学和预测毒理学中心

• 批准号: 8393965
• 负责人: Andre Elias Nel
• 金额: $ 7.56万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-24 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393965
• 关键词: Biological Availability; Biology; Biometry; Cells; Cellular Structures; Cellular biology; Computer Simulation; Cytolysis; Data; Dose; Engineering; Fibrosis; Future; Generations; Goals; Health; Image; In Vitro; Inflammation; Inhalation Exposure; Injury; Lead; Libraries; Link; Lung; Lytic; Machine Learning; Mathematics; Membrane; Metals; Methods; Modeling; Molecular; Multivariate Analysis; Mus; Organ; Outcome; Oxidative Stress; Pathway interactions; Performance; Play; Pneumonia; Property; Rattus; Research Project Grants; Risk; Rodent; Role; Science; Screening procedure; Signal Pathway; Signal Transduction; Silicon Dioxide; Structure; Tissues; Toxic effect; Toxicology; base; cellular imaging; chemical property; combinatorial; computer science; cytotoxicity; hazard; high throughput screening; in vivo; mathematical model; metal oxide; multidisciplinary; nano; nanobiology; nanomaterials; nanoparticle; physical property; predictive modeling; statistics

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).

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，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、数学和计算机科学的专业知识，总体目标是从根本上了解精心挑选的ENM文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的生物-物理化学相互作用可能如何导致肺毒性。这一目标将通过获得、合成和表征成分和组合ENM文库来实现，这些文库侧重于提名的金属、金属氧化物和二氧化硅纳米粒子的主要物理化学性质(Science Core)，假设这些纳米粒子通过产生氧化应激、炎症、信号通路激活和膜溶解在肺部毒性中发挥作用。这些努力将得到电子计算机建模的帮助，该模型使用热图、数学模型和机器学习来执行危险排名和风险预测。该中心的主要目标是：(1)建立一个总体的预测毒理学范式，其定义是基于体外和计算机方法(综合中心工作)对ENM的体内毒性潜力的评估；(2)建立快速的细胞筛选和成像，以确定导致上述损伤途径的生物利用度和参与的ENM的组成和组合特性(项目1)；(Iii)通过对啮齿动物肺部的滴注和吸入暴露，确定将ENM与体外损伤机制联系起来的结构-特性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)建立矽中毒模型，利用快速通量筛查和细胞成像数据的多变量分析，显示可用于开发“纳米QSARs”以进行概率风险排序的关系(项目3)。