Engineered nanomaterials (ENM) have unique properties that can cause adverse health effects. Due to their small size and potential for airborne dispersion, inhalation exposure to ENM might contribute to the increased incidence and/or exacerbation of allergic airway disease. The overall goal of this project is to develop a multi- level toxicity testing platform for ENM that includes in vivo measurement of allergic airway disease in mice, in vitro measurement of T cell activation, high-throughput measurement of ENM's interactions with bilayer lipid membranes (BLM) that mimic cell membranes, and in silico prediction of ENM's molecular properties. The overarching hypothesis that ENM possess adjuvant-like properties that promote allergic airway disease will be tested using five specific aims (SA). SA1 is to synthesize well-characterized ENM having controlled functional groups that catalyze redox reactions or activate membrane receptors. SA2 is to determine the adjuvant potential of ENM on allergic airway sensitization and asthma-like disease in mice. SA3 is to determine the effects of ENM on dendritic cell-induced activation and effector function of CD4+ and CD8+ T cells. SA4 is to measure the direct effects of ENM on synthetic bilayer lipid membranes. SA5 is to develop and validate mathematical models that can correlate ENM physicochemical properties with their biological and toxicological effects at the animal, cell, and membrane levels for health risk assessment. Biodegradable poly(propargyl glycolide) nanoparticles will be synthesized and coated with chemical groups (lipopolysaccharide (LPS) and quinone) to generate ENM likely to stimulate the immune response. LPS bind to receptor proteins on cell membranes and trigger cellular uptake by endocytosis, and quinones can trigger oxidation-reduction reactions, including production of reactive oxygen species by immune cells. A multi-tiered approach will be used to determine whether addition of LPS and quinone to ENM increases the ENM's ability to promote airway disease by (1) increasing the murine immune system's response to the antigen ovalbumin, (2) increasing T cell activation by dendritic cells in response to ovalbumin, and (3) modifying the ELM's molecular interactions with BLM. Mice will be exposed to the ENM by inhalation, and severity of allergic airway disease will be histopathologically, morphometrically and biochemically assessed. Dendritic cells will be exposed to the ENM, and their ability to activate T cells will be measured using fluorescence assisted flow cytometry. BLM will be deposited on electrodes and exposed to the ENM. The resulting interactions between the ENM and BLM will be measured in a high-throughput mode using cyclic voltammetry and electrical impedance spectroscopy. Theoretical models will be developed that describe the molecular properties of the ENM and their interactions with cellular components. These models will be used to analyze the experimental data and help elucidate mechanisms by which ENM induce toxic effects.
This project will provide fundamental insight into how a nanoparticle's physical and chemical properties determine its ability to enhance allergic airway disease like asthma. This insight will aid in setting health and safety standards for engineered nanomaterials, provide new high- throughput methods for nanoparticle detection and safety screening, and facilitate design of new nanomaterials that simultaneously meet safety standards and exhibit desirable performance properties needed for commercial applications.
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