Predictive Toxicological Paradigm for Chronic Nanoparticle Injury in the Lung

肺部慢性纳米颗粒损伤的预测毒理学范式

• 批准号: 8575920
• 负责人: Andre Elias Nel
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8575920
• 关键词: Accounting; Achievement; Acute; Acute Lung Injury; Address; Animals; Artificial nanoparticles; Autophagocytosis; Autophagosome; Awareness; Categories; Cell membrane; Chemistry; Chronic; Data; Decision Making; Development; Disease; Dissection; Engineering; Epithelial; Exercise; Functional disorder; Goals; Health; Human; Hydration status; Hydrogen Bonding; Inflammatory; Injury; Knowledge; Lead; Link; Literature; Lung; Lysosomes; Macrophage Activation; Mediating; Membrane; Mesenchymal; Mission; Mitochondria; Modification; Nanotechnology; Outcome; Oxides; Pathway interactions; Play; Pneumonia; Process; Production; Property; Public Health; Pulmonary Fibrosis; Quality Control; Research; Risk Reduction; Role; Safety; Science; Silicon Dioxide; Siloxanes; Solvents; Speed; Structure; Structure-Activity Relationship; Surface; Testing; Toxic effect; Transition Elements; Variant; Water; Work; base; cell injury; design; disability; hazard; human disease; in vivo; innovation; lung injury; metal oxide; nano; nanocrystal; nanomaterials; nanoparticle; nanoscale; new technology; reconstruction; response to injury; silanol

DESCRIPTION (provided by applicant): Currently there is insufficient knowledge of how material properties at the nanoscale level could induce chronic toxicological injury. Addressing this knowledge gap is important for the safety assessment of engineered nanomaterials (ENMs) and the implementation of risk reduction strategies. Our long-term goal is to develop a fundamental understanding of the mechanisms by which industrially important ENMs mediate lung injury and use of this information to formulate predictive toxicological approaches that can be used for ENM safety assessment and safer design. The overall objective of this competitive renewal application is to develop a predictive paradigm for chronic pulmonary toxicity that is premised on the unique properties of rare earth oxide (REO) and fumed silica NPs towards engaging the NLRP3 inflammasome and disrupting the autophagy quality control mechanisms that regulate these inflammasomes. Our central hypothesis is that the (i) biocatalytic transformation of REOs into highly reactive REO-PO4 nanocrystals in the lysosome, and (ii) hydration- dependent reconstruction and display of highly reactive silanols on fumed silica NPs are responsible for sustained NRLP3 activation and autophagy blockade, leading to macrophage activation, epithelial- mesenchymal transition (EMT), and ultimately delayed or chronic pulmonary inflammation and fibrosis. The rationale for the proposed research is that, once it is known how unique nanoscale properties of the fumed silica and oxide NPs induce chronic lung injury, we can use this predictive paradigm for expedited safety assessment as well as safer design of these materials. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: Aim 1: To develop a predictive toxicological paradigm for chronic lung injury that is premised on rare earth oxide NP properties leading to lysosomal injury, NLRP3 inflammasome assembly and autophagy dysfunction. This scenario will be compared against acute lung injury by transition metal oxides. Aim 2: To develop a predictive toxicological paradigm that relates the framework chemistry and hydration status of fumed silica nanoparticles to a lysosome-independent mechanism of NLRP3 inflammasome activation, which originates at the surface membrane. Aim 3: To demonstrate that systematic control of the precursor chemistry and hydration conditions during flame spray pyrolysis (FSP) can be used to produce safer fumed silica NPs. Our approach is innovative, because we use a predictive toxicological paradigm that is premised on structure-activity relationships (SARS) linking cellular injury response pathways to the pathophysiology of chronic lung injury. The proposed research is significant because: (i) we will introduce a robust, quantitative scientific platform to assess ENM safety; (ii) ability to predict in vivo toxicological scenarios that reduce the need for expensive chronic exposure studies in animals; (iii) ability to speed up the rate of safety assessment and regulatory decision-making, commensurate with the number of new applications based on above material categories; (iv) development of SARs for the safer design of fumed silica NPs.

描述（由申请人提供）：目前对纳米级水平的材料特性如何引起慢性毒理学损伤的了解不足。解决此知识差距对于工程纳米材料（ENM）的安全评估和实施降低风险策略至关重要。我们的长期目标是对具有工业重要的ENM介导肺损伤的机制进行基本理解，并使用此信息来制定可用于ENM安全评估和更安全的设计的预测毒理学方法。这种竞争性更新应用的总体目的是为慢性肺毒性提供预测范式，该典型范围在稀土氧化物（REO）（REO）的独特特性和烟雾硅NP的独特特性中发展，以使NLRP3炎症体和破坏调节这些炎症的自噬质量控制机制。 Our central hypothesis is that the (i) biocatalytic transformation of REOs into highly reactive REO-PO4 nanocrystals in the lysosome, and (ii) hydration- dependent reconstruction and display of highly reactive silanols on fumed silica NPs are responsible for sustained NRLP3 activation and autophagy blockade, leading to macrophage activation, epithelial- mesenchymal transition （EMT），并最终延迟或慢性肺部炎症和纤维化。拟议的研究的理由是，一旦知道了烟雾二氧化硅和氧化物NP的独特纳米级特性如何诱导慢性肺损伤，我们就可以使用这种预测范式来加快安全性评估以及对这些材料的更安全设计。在强有力的初步数据的指导下，将通过追求三个特定目的来检验该假设：目标1：为慢性肺损伤开发预测性毒理学范式，前提是在稀土氧化物NP的特性上，导致溶酶体损伤，NLRP3炎症体组装和自动型功能障碍。这种情况将与过渡金属氧化物与急性肺损伤进行比较。目的2：开发一种将框架化学和水合二氧化硅纳米颗粒与NLRP3炎性体激活的溶酶体独立机制相关的预测毒理范式，该机制起源于表面膜。目标3：要证明，在火焰喷雾热解（FSP）过程中对前体化学和水合条件的系统控制可用于产生更安全的烟气NP。我们的方法具有创新性，因为我们使用的预测毒理学范式前提是在结构活性关系（SARS）上连接细胞 对慢性肺损伤病理生理学的损伤反应途径。拟议的研究很重要，因为：（i）我们将引入一个可靠的，定量的科学平台来评估ENM安全； （ii）能够预测体内毒理学情景，以减少对动物中昂贵的慢性暴露研究的需求； （iii）能够加快安全评估和监管决策的速度，与基于上述材料类别的新应用数量相称； （iv）开发SARS，用于更安全的二氧化硅NP。