The Center for Nanobiology and Predictive Toxicology has assembled a multidisciplinary team with expertise in nanomaterial science, toxicology, cell biology, high throughput screening, biostatistics, mathematics and computer science with the overall goal of gaining fundamental understanding of how the physical and Chemical properties of carefully selected ENM libraries relate to interactions with cells and cellular structures, including how these bio-physicochemical interactions at the nano-bio interface may lead to pulmonary toxicity. This goal will be executed through the acquisition, synthesis and characterization of compositional and combinatorial ENM libraries that focus on the major physicochemical properties of nominated metal, metal oxide and silica nanoparticles {Scientific Core), hypothesized to play a role in pulmonary toxicity through the generation of oxidative stress, inflammation, signal pathway activation and membrane lysis. These efforts will be assisted by in silico modeling that use heatmaps, mathematical models and machine learning to perform hazard ranking and risk prediction. The major objectives of the Center are: (i) To establish an overarching predictive toxicological paradigm, which is defined as the assessment of in vivo toxic potential of ENM based on in vitro and in silico methods (integrated center effort);(ii) To establish rapid throughput cellular screening and conduct imaging to identify compositional and combinatorial ENM properties that lead to bioavailability and engagement of the injury pathways discussed above (Project 1);(iii) To establish through the performance of instillation and inhalation exposures in the rodent lung how the structure-property relationships linking ENM to in vitro injury mechanisms may be predictive of pulmonary inflammation, fibrosis and cytotoxicity in a dose-dependent fashion (Project 2);(iv) To develop in silico toxicity models that utilize multivariate analysis of the rapid throughput screening and cellular imaging data to show the relationships that can be used to develop "nano-QSARs" for probabilistic risk ranking (Project 3).

Public Health Relevance

We propose a center to study how properties of engineered nanomaterials may lead to lung health effects by creating harmful interactions in cells and tissues that will come into contact with these materials. This will be accomplished by a multi-disciplinary team who will use their expertise in nanomaterial science, biology, toxicology, imaging, statistics and computer science to integrate above goals into a predictive model that projects from what is happening in cells to what may happen in the lung.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19ES019528-05
Application #
8668954
Study Section
Special Emphasis Panel (ZES1-SET-V (03))
Program Officer
Nadadur, Srikanth
Project Start
2010-09-24
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$1,029,385
Indirect Cost
$326,591
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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