Carbon nanomaterial-induced malignant transformation and lung carcinogenesis

碳纳米材料诱导的恶性转化和肺癌发生

• 批准号: 1434503
• 负责人: Yon Rojanasakul
• 金额: $ 30万
• 依托单位: West Virginia University Research Corporation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1434503&HistoricalAwards=false
• 关键词: Carbon; nanomaterial; induced; malignant; transformation

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.

PI：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发生 工程纳米材料，包括碳纳米管 (CNT)，已越来越多地用于各种应用。然而，人们尚不清楚碳纳米管对健康造成不良影响的风险，例如碳纳米管的潜在致癌性。 PI 和 Co-PI 开发了一种慢性暴露模型，其中人肺上皮细胞（CNT 致癌的主要细胞靶标）长期暴露于低剂量生理相关浓度的 CNT。 PI和Co-PI将检查物理化学特性（长度、金属杂质、表面电荷、表面化学修饰等）如何诱导细胞恶性转化，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，这种方法可以提供可靠预测 CNT 致癌性的实验模型和测定方法，同时还为 CNT 诱导的致癌作用建立特定的生物标志物。这反过来将推进更安全的设计策略和工人保护问题。公开演讲和总结报告将在西弗吉尼亚大学、NanoSAFE 和 NIOSH 网站上发布，以非技术术语揭示该项目的基本发现，而预期的外展工作将包括代表性不足的群体。在该提案中，PI 假设 CNT 致癌性取决于其理化特性以及通过间皮素（MSLN，一种已知的石棉诱发癌症的生物标志物）和基质金属蛋白酶 (MMP-2) 依赖性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）开发体外模型来预测CNT致癌性，并确定恶性转化和肿瘤形成的诱导是否可以预测体内致瘤反应； 2）确定MSLN在CNT诱导的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 作为组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预测体内致瘤反应。这是一项创新提案，解决了一个重要问题，即纳米材料特性与人类长期疾病的关系。其他优势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，使用共享粒子样本对于复制和后续研究至关重要。