Membrane Receptor-Directed Nanomaterial-Cell Interactions
EMSL Project ID
40073
Abstract
The global market for nanotechnology is expected to grow to ~$3 trillion by 2015 and with the increased fabrication and usage of nanomaterials the potential for exposure of nanotechnology workers and consumers will increase. Unfortunately, it is not feasible in a financial or timely manner to evaluate the potential health effects of engineered nanomaterials (ENM) on a case-by-case basis using traditional animal testing methods. The mechanisms by which some, but not all ENM cause various pathologies are not understood in animal models thus creating uncertainty with the use of in vitro models. Such mechanistic information is needed to drive development of high throughput predictive experimental systems and models for hazard analysis and risk assessment. Our overall hypothesis is that macrophages and the inflammasome pathway are central to the development of the inflammatory response following exposure to ENM. Our overall goal is to determine the role of specific SR in regulating the cell uptake and trafficking of ENM in support of developing models for hazard analysis. EMSL provides unique capabilities that enable quantitative cellular, molecular, structural and chemical imaging at the nano-scale. We propose to apply multi-spectral high sensitivity fluorescence imaging in live cells to follow ENM movement within cells in real time. Electron and ion microscopy will also be employed to determine the fate and chemical/ structural changes of the ENM within the cellular environment at atomic resolution. Markers of lysosomal integrity and inflammasome activity will be used to determine the relationship between ENM trafficking and inflammatory signaling. Finally, multi-spectral flow cytometry will be used to quantify the relationships between membrane receptor levels, cellular uptake (dose), and inflammasome activity with single cell resolution. These data will be used to develop dose-response models to facilitate identification of threshold cellular ENM doses, which can be used for hazard analysis and risk extrapolation.
Project Details
Project type
Large-Scale EMSL Research
Start Date
2010-10-01
End Date
2012-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Orr G, WB Chrisler, KJ Cassens, R Tan, BJ Tarasevich, LM Markillie, RC Zangar, and BD Thrall. 2011. "Cellular Recognition and Trafficking of Amorphous Silica Nanoparticles by Macrophage Scavenger Receptor A." Nanotoxicology 5(3):296-311. doi:10.3109/17435390.2010.513836
Xia T, RF Hamilton, JC Bonner, ED Crandall, AC Elder, F Fazlollahi, TA Girtsman, K Kwang, S Mitra, SA Ntim, G Orr, M Tagmount, AJ Taylor, D Telesca, A Tolic, CD Vulpe, AJ Walker, X Wang, FA Witzmann, N Wu, Y Xie, JI Zink, A Nel, and A Holian, Ph.D.. 2013. "Interlaboratory Evaluation of in Vitro Cytotoxicity and Inflammatory Responses to Engineered Nanomaterials: The NIEHS Nano GO Consortium." Environmental Health Perspectives 121(6):683-690.