Many carbon nanotubes have been shown to cause lung inflammation and fibrosis, but the mechanisms responsible for these effects are not well understood. Furthermore, the ability to manufacture carbon nanotubes (CNT) in many different formats has created an urgency to develop better understanding of CNT safety and hazard ranking. We have described that CNT activated cause phagolysosomal membrane permeability (LMP) leading to release of cathepsin B and NLRP3 inflammasome activation. However, the mechanisms responsible for causing LMP and additional events controlling the inflammatory response (e.g., autophagy) are not well described, thus limiting progress in the field of nanotoxicology. The overall objective of this project is to develop well-characterized libraries of multi-walled and single-walled CNT with controlled properties (physical and chemical) that represent the most commercially viable forms and use these materials to provide insight into a mechanistic understanding and structure activity relationship of CNT toxicity both in vitro and in vivo. Our central hypothesis is that the biological responses will be dependent on specific properties of CNT and these properties regulate phagolysosomal membrane permeability (LMP) and autophagy. Furthermore, we propose that CNT cause LMP by affecting cholesterol trafficking. Therefore, we propose that we will be able to predict the proinflammatory and profibrotic activity of CNT based on these properties. The central hypothesis will be tested with the following aims:
Aim 1 : Develop a comprehensive library of fully characterized CNT with specific physicochemical characteristics.
Aim 2 : Determine the mechanism of bioactivity of CNT developed in Aim 1 and characterize the uptake, relative bioactivity of the CNT to cause LMP, NLRP3 activation (IL-1? release) and autophagy.
Aim 3 : Evaluate the mechanism of in vivo pathology of selected CNT. The long-term goal of our interdisciplinary team is to develop an approach to toxicity prediction based on physicochemical properties of CNT. This strategy can then be used for hazard ranking as well as safe design of the CNT forms with high commercial potential.

Public Health Relevance

The proposed studies will elucidate the mechanisms to explain how carbon nanotubes cause inflammation. This information will be used in combination with a library of various CNT with known properties to serve as a guideline for hazard ranking and safer design. Such results can be used to commercialize this valuable material in a way that is not hazardous to public health and provide guidelines to regulatory agencies that can be extended to other high aspect ratio nanomaterials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES023209-05
Application #
9478691
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nadadur, Srikanth
Project Start
2014-08-01
Project End
2019-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Montana
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
010379790
City
Missoula
State
MT
Country
United States
Zip Code
59812
Intrchom, Worawit; Thakkar, Megha; Hamilton Jr, Raymond F et al. (2018) Effect of Carbon Nanotube-Metal Hybrid Particle Exposure to Freshwater Algae Chlamydomonas reinhardtii. Sci Rep 8:15301
Chandra, Boggarapu Praphulla; Wu, Zheqiong; Ntim, Susana Addo et al. (2018) The Effect of Functional Group Polarity in Palladium Immobilized Multiwalled Carbon Nanotube Catalysis: Application in Carbon-Carbon Coupling Reaction. Appl Sci (Basel) 8:
Azizighannad, Samar; Mitra, Somenath (2018) Stepwise Reduction of Graphene Oxide (GO) and Its Effects on Chemical and Colloidal Properties. Sci Rep 8:10083
Hamilton, Raymond F; Wu, Zheqiong; Mitra, Somenath et al. (2018) The Effects of Varying Degree of MWCNT Carboxylation on Bioactivity in Various In Vivo and In Vitro Exposure Models. Int J Mol Sci 19:
Wang, Zhiqian; Meng, Xianyang; Chen, Kun et al. (2018) Synthesis of Carbon Nanotube Incorporated Metal Oxides for the Fabrication of Printable, Flexible Nickel-Zinc Batteries. Adv Mater Interfaces 5:
Zhu, Yuan; Chen, Kun; Yi, Chen et al. (2018) Dry reforming of methane over palladium-platinum on carbon nanotube catalyst. Chem Eng Commun 205:888-896
Bunderson-Schelvan, Melisa; Holian, Andrij; Hamilton Jr, Raymond F (2017) Engineered nanomaterial-induced lysosomal membrane permeabilization and anti-cathepsin agents. J Toxicol Environ Health B Crit Rev 20:230-248
Wu, Zheqiong; Wang, Zhiqian; Yu, Fang et al. (2017) Variation in chemical, colloidal and electrochemical properties of carbon nanotubes with the degree of carboxylation. J Nanopart Res 19:
Jessop, Forrest; Hamilton Jr, Raymond F; Rhoderick, Joseph F et al. (2017) Phagolysosome acidification is required for silica and engineered nanoparticle-induced lysosome membrane permeabilization and resultant NLRP3 inflammasome activity. Toxicol Appl Pharmacol 318:58-68
Bai, Wei; Wu, Zheqiong; Mitra, Somenath et al. (2016) Effects of multiwalled carbon nanotube surface modification and purification on bovine serum albumin binding and biological responses. J Nanomater 2016:

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