Carbon nanomaterial-induced malignant transformation and lung carcinogenesis

项目负责人：Rojanasakul， Yon提案编号：1434503机构：西弗吉尼亚大学研究公司标题：碳纳米材料诱导的恶性转化和肺癌工程纳米材料，包括碳纳米管（CNTs），已越来越多地用于各种应用。然而，碳纳米管潜在致癌性等不良健康影响的风险尚不清楚。PI和Co-PI建立了一个慢性暴露模型，在该模型中，人肺上皮细胞（碳纳米管致癌的主要细胞靶点）长期暴露于低剂量的生理相关浓度的碳纳米管。PI和Co-PI将研究物理化学性质（长度，金属杂质，表面电荷，表面化学修饰等）如何诱导细胞中的恶性转化，寻找潜在的生物标志物，并研究这些生物标志物在诱导转化和肿瘤中的作用。如果成功，该方法可以提供可靠预测碳纳米管致癌性的实验模型和分析方法，同时还可以为碳纳米管诱导的致癌性建立特定的生物标志物。这反过来将推进设计安全策略和工人保护问题。以非技术术语揭示该项目的基本发现的公开演讲和总结报告将发布在西弗吉尼亚大学、NanoSAFE和NIOSH的网站上，而预期的推广工作将包括代表性不足的群体。在这项提议中，pi假设碳纳米管的致癌性依赖于它们的物理化学性质和通过间皮素（MSLN，一种已知的石棉诱导癌症的生物标志物）和基质金属蛋白酶（MMP-2）依赖机制诱导靶肺细胞恶性转化的能力。为了验证这一假设，pi将把研究分为3个目标：1)建立体外模型来预测碳纳米管的致癌性，并确定诱导恶性转化和肿瘤形成是否可以预测体内的致瘤反应；2)确定MSLN在碳纳米管诱导转化和肿瘤中的作用，并阐明其潜在机制；3)评估使用MSLN和MMP-2作为联合生物标志物来预测CNT致癌性，并确定CNT对MSLN和MMP-2诱导的影响，以了解这种诱导是否可以预测体内的致瘤反应。这是一个创新的提议，解决了一个重要的问题，即纳米材料特性与长期人类疾病的关系。其他优点包括使用存档的参考材料和可与体内暴露进行比较的实际剂量。此外，共享粒子样本的使用对于复制和后续研究都是必不可少的。

PI: Rojanasakul, Yon Proposal Number: 1434503Institution: West Virginia University Research CorporationTitle: Carbon nanomaterial-induced malignant transformation and lung carcinogenesis Engineered nanomaterials, including carbon nanotubes (CNTs), have increasingly been used for a variety of applications. However, the risk of adverse health effects, such as from the potential carcinogenicity of CNTs are not understood. The PI, and Co-PI, have developed a chronic exposure model in which human lung epithelial cells, a major cellular target of CNT carcinogenesis, are exposed, over long-term, to low-dose physiologically relevant concentrations of CNTs. The PI and Co-PI will examine how the physicochemical properties (length, metal impurity, surface charge, surface chemical modifications, etc) may induce malignant transformations in cells, look for potential biomarkers, and investigate the role of those biomarkers in induced transformations and tumors. If successful, this approach can provide experimental models and assay methods that reliably predict CNT carcinogenicity, while also establishing specific biomarkers for CNT-induced carcinogenesis. This, in turn will advance both safer-by-design strategies and worker protection issues. Public presentations and summary reports, revealing the fundamental findings from this project in nontechnical terms, will be posted on the West Virginia University, NanoSAFE, and NIOSH websites, while the intended outreach efforts include underrepresented groups. In this proposal, the PIs hypothesize that CNT carcinogenicity is dependent on their physicochemical properties and ability to induce malignant transformation of target lung cells through mesothelin (MSLN, a known biomarker for asbestos induced cancer) and matrix metalloproteinase (MMP-2) dependent mechanisms. To verify this hypothesis, the PIs will break down the investigations into 3 aims: 1) Develop in vitro models to predict CNT carcinogenicity, and determine if the induction of malignant transformation and tumor formation is predictive of in vivo tumorigenic responses; 2) Determine the role of MSLN in CNT-induced transformations and tumors, and elucidate the underlying mechanisms; and 3) Evaluate the use of MSLN and MMP-2 as combination biomarkers to predict CNT carcinogenicity and determine the effect of CNT on MSLN and MMP-2 induction to see if such induction is predictive of in vivo tumorigenic responses. This is an innovative proposal that addresses an important question, the relationship of nanomaterial properties to long-term human disease. Additional strengths include the use of archived reference materials and realistic doses that can be compared to in vivo exposures. In addition, the use of shared particle samples is essential for both replication and for follow-up studies.