Mechanisms of Mast Cell Directed Carbon Nanotube Toxicity

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 DESCRIPTION (provided by applicant): Engineered nanomaterials (ENMs) have unique physicochemical properties with potential to impact diverse aspects of society. While the research and proposed applications of ENMs continue to grow rapidly, the health and safety of ENMs still remains a major concern to the public as well as to policy makers and funding agencies. While there has been considerable investigation into the properties of ENMs that elicit toxicity, little work has focused on the ability of ENMs to promote or exacerbate allergic disease. Mast cell activation, which is central to development of allergic disease, has been an impediment to a number of pharmaceuticals and will likely represent a challenge for nanomedicines. Consequently, research on the health and safety implications of ENMs must address the potential for nanomedicines, nano-based consumer products or occupational exposures and the impact on initiation of allergic disease or exacerbation of underlying allergic diseases such as asthma. We have established, through the first cycle of this grant, that certain ENMs elicit mast cell activation either directly (via scavenger receptor B1) or indirectly (via IL-33) leading to adverse pulmonary and cardiovascular outcomes. Based on these findings, we have begun to investigate the properties of ENMs that promote mast cell degranulation or IL-33 production. Our preliminary data has suggested that the density of states or electronic energy levels of the ENM, as a yet unrecognized physicochemical property, contribute to mast cell degranulation through charge transfer to cell surface receptors or proteins. In addition, through preliminary studies, we have found that mast cell responses to ENMs are significantly variable across strains of inbred mice suggesting these responses are polygenic in nature. For this project, we hypothesize that ENM-directed mast cell activation is driven by key physical properties and chemical process at the nano-bio interface, which initiate novel signaling pathways, distinct from other pathogens/bulk allergens, driven by scavenger receptor B1 and this response is largely influenced by genetics. Our objectives are: 1) determine the ENM physicochemical properties responsible for mast cell activation through use of combinatorial library of ENMs; 2) establish the contribution of novel signaling pathways mediated through scavenger receptor B1 in the mast cell response to ENMs through cellular signaling studies; 3) elucidate the role of genetics in mast cell responses to ENM exposure using genome wide association analysis and transcriptomics with a hybrid mouse diversity panel of inbred and recombinant inbred strains. Understanding these mechanisms will allow us to design better models and in vitro screening tools to predict ENM toxicity, which will be important for risk assessment. More importantly, by gaining a more in depth understanding of the physicochemical properties that lead to mast cell degranulation, we will be able to engineer materials to prevent mast cell responses.