The objective of this proposal is to identify novel biomarkers and molecular mechanisms of multi-walled carbon nanotube (MWCNT)-induced pulmonary diseases, including fibrosis, for early detection and treatment interventions. MWCNT have been widely used for various industrial applications. However, concern over potential MWCNT-induced toxicity has emerged, particularly due to the structural similarity between asbestos and MWCNT. In our preliminary studies, exposure of mice to MWCNT by pharyngeal aspiration results in significant pulmonary inflammation, damage, and fibrosis at 56 days post-exposure. We have identified MWCNT-induced gene signatures in the mouse model that could predict human lung cancer risk and progression. In the computational evaluation of more than 800 pathways, VEGF, ICAM-1, MCP-1, and TGF- are among the most significantly represented pathways in the mouse model. The involvement of these signaling pathways has been further validated in MWCNT-treated human small airway epithelial cells (SAEC). A co-culture model of SAEC with human microvascular endothelial cells (HMVEC) was recently developed by our laboratory to elucidate mechanisms for MWCNT-induced cellular response. Nevertheless, the long-term pulmonary responses to MWCNT in mice and their underlying molecular mechanisms remain to be resolved. Moreover, there are currently no clinically available biomarkers for early detection and no effective treatment inventions for MWCNT-induced pulmonary diseases, particularly lung fibrosis. We hypothesize that genomic profiling and computational toxicology analysis of in vitro and in vivo studies can identify novel mechanisms and biomarkers predictive of MWCNT-induced pulmonary injuries in humans, which will lead to early diagnostic detection and treatment interventions for MWCNT-induced pulmonary diseases, including fibrosis. We will utilize multidisciplinary approaches, including in vivo animal toxicology assays, in vitro cellular toxicology assays, and computational modeling, to establish in vitro genomic signatures predictive of MWCNT-induced pulmonary diseases in the in vivo animal model and in humans and to explore the potential molecular targets for early treatment interventions.
Aim 1 will evaluate the pulmonary dose-response and time course responses to MWCNT exposure in mice for up to 1 year.
Aim 2 will determine the molecular mechanisms of MWCNT- induced injuries to the lung using an alveolo-capillary co-culture model.
Aim 3 will identify mechanism-based gene signatures predictive of MWCNT-induced human pulmonary diseases using in vivo, in vitro, and patient data for early detection and treatment interventions.
Aim 4 will perform integrated analyses of MWCNT-induced mRNA and miRNA changes and identify miRNA markers for early detection of MWCNT-induced lung fibrosis using non-invasive blood tests. We anticipate that this project will transform toxicological research of MWCNT- induced pulmonary diseases into strategies for environmental health protection and intervention. Results will fill th gap between in vivo/in vitro MWCNT-induced toxicity studies and risk assessment in humans.
Multi-walled carbon nanotubes (MWCNT) have broad industrial applications. This project will assess the risk of MWCNT exposure in humans through animal and human cell model studies, and will develop early detection and treatment strategies for MWCNT-induced lung diseases, particularly fibrosis.
|Snyder-Talkington, Brandi N; Dong, Chunlin; Sargent, Linda M et al. (2016) mRNAs and miRNAs in whole blood associated with lung hyperplasia, fibrosis, and bronchiolo-alveolar adenoma and adenocarcinoma after multi-walled carbon nanotube inhalation exposure in mice. J Appl Toxicol 36:161-74|
|Snyder-Talkington, Brandi N; Dong, Chunlin; Porter, Dale W et al. (2016) Multiwalled carbon nanotube-induced pulmonary inflammatory and fibrotic responses and genomic changes following aspiration exposure in mice: A 1-year postexposure study. J Toxicol Environ Health A 79:352-66|
|Pirela, Sandra V; Lu, Xiaoyan; Miousse, Isabelle et al. (2016) Effects of intratracheally instilled laser printer-emitted engineered nanoparticles in a mouse model: A case study of toxicological implications from nanomaterials released during consumer use. NanoImpact 1:1-8|
|Snyder-Talkington, Brandi N; Dong, Chunlin; Zhao, Xiangyi et al. (2015) Multi-walled carbon nanotube-induced gene expression in vitro: concordance with in vivo studies. Toxicology 328:66-74|
|Dymacek, Julian; Snyder-Talkington, Brandi N; Porter, Dale W et al. (2015) mRNA and miRNA regulatory networks reflective of multi-walled carbon nanotube-induced lung inflammatory and fibrotic pathologies in mice. Toxicol Sci 144:51-64|
|Dymacek, Julian; Guo, Nancy Lan (2014) Integrated miRNA and mRNA Analysis of Time Series Microarray Data. ACM BCB 2014:122-127|
|Pacurari, Maricica; Addison, Joseph B; Bondalapati, Naveen et al. (2013) The microRNA-200 family targets multiple non-small cell lung cancer prognostic markers in H1299 cells and BEAS-2B cells. Int J Oncol 43:548-60|
|Snyder-Talkington, Brandi N; Pacurari, Maricica; Dong, Chunlin et al. (2013) Systematic analysis of multiwalled carbon nanotube-induced cellular signaling and gene expression in human small airway epithelial cells. Toxicol Sci 133:79-89|
|Snyder-Talkington, Brandi N; Schwegler-Berry, Diane; Castranova, Vincent et al. (2013) Multi-walled carbon nanotubes induce human microvascular endothelial cellular effects in an alveolar-capillary co-culture with small airway epithelial cells. Part Fibre Toxicol 10:35|
|Snyder-Talkington, Brandi N; Dymacek, Julian; Porter, Dale W et al. (2013) System-based identification of toxicity pathways associated with multi-walled carbon nanotube-induced pathological responses. Toxicol Appl Pharmacol 272:476-89|
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