ARRA - Bioactivity of Engineered Fiber-Shaped Nanomaterials

Nanomaterials (NM) continues to be rapidly developed for a wide variety of potential uses. NM have unique properties based on approaching molecular size that also cause them to have unique interactions with biological systems. To date there is limited information to explain mechanisms of interaction with biological systems and our ability to predict what properties of NM constitute safe NM remains questionable. Consequently, our ability to evaluate the health and safety of NM and predict in vivo outcomes from in vitro testing alone remains difficult. Our studies support the hypothesis that inflammatory NM are defined by shape (e.g., fibrous NM), influence by charge and act as danger signals to macrophages causing activation of the Nalp3 inflammasome leading to IL-12 mediated lung and neuropathology. This hypothesis will be tested using an interdisciplinary team approach with four Aims. 1: Synthesize and characterize bare and surface-coated fibre-shaped/sphere-shaped NM including TiO2 and ZnO nanowires/nanospheres as well as multiwalled carbon nanotubes; 2: Demonstrate that in contrast to nanospheres, nanowires activate the Nalp3 inflammasome in vitro and increasing the negative surface charge (more hydrophilic NM) should decrease their inflammatory activity; 3: Demonstrate in vivo that nanowires, but not nanospheres, induce Nalp3 inflammasome mediated IL-12 release causing both lung pathology and neuropathology. Furthermore, negative surface modified NM should be less bioactive in vivo; and 4: Develop statistical modeling methods to correlate the in vitro and in vivo toxicity with the physico-chemical properties of NM (i.e., chemical composition, shape and surface coating). These studies will combine materials science, in vitro and in vivo biochemical and mechanistic studies with modeling to establish that the shape and surface charge of NM can influence the ability of NM to activate the Nalp3 inflammasome resulting in local and systemic pathology. Furthermore, we propose to establish a predictive model that will allow for more efficient and rapid in vitro screening of NM for safety testing. The mechanistic studies will establish the mechanism by which biologically incompatible NM cause inflammation and provide for potential therapeutic interventions. ) PUBLIC HEALTH RELEVANCE: Relevance This study will examine the biological activity and mechanism of action of selected engineered nanomaterials in order to help protect human health and develop safe nanomaterials.