Grant Abstract: Bioactivity and mechanistic studies using a comprehensive and well characterized

Grant Number: 5R01ES023209-03
PI Name: Holian
Project Title: Bioactivity and mechanistic studies using a comprehensive and well characterized

Abstract: As described in our Parent R01 (ES023209) “Bioactivity and mechanistic studies using a comprehensive and well characterized carbon nanotube library”, there is a great deal of interest in human health effects following exposure to carbon nanotubes (CNT) and CNT serve as a relevant initiator of chronic disease. CNT have been shown to cause inflammation that rapidly progresses to lung fibrosis and possibly other systemic diseases. Our studies have demonstrated that CNT cause phagolysosomal membrane permeability (LMP) leading to release of cathepsin B and NLRP3 inflammasome activation as initial events in lung inflammation. This is a central mechanism that has been proposed to regulate lung and many chronic inflammatory diseases. Determining the impact of dietary choices on this process will provide important information regarding external factors that may ultimately alter health outcomes. Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid (PUFA) that is commonly used as a dietary supplement and that modulates membrane integrity. It is our central hypothesis that supplements known to modify cholesterol content in cellular membranes will modulate the effects of LMP caused by exposure to bioactive CNT. This, in turn, will provide insight into how diet might impact mechanisms of inflammation following environmental exposures. Our overall rationale is that evaluating the role of cholesterol-­modulating dietary supplements in disease outcomes will give us an improved mechanistic understanding of the potential health impacts of these dietary supplements. Therefore, we propose to examine how DHA may influence disease outcomes following CNT exposure with a focus on LMP and NLRP3 inflammasome activation in macrophages. There are two aims in our studies: 1: Determine the influence of the dietary supplement, DHA, on MWCNT-­induced pathology and inflammatory response in a murine model;; 2: Evaluate the influence of DHA on MWCNT-­induced lysosomal membrane instability in J774.2 murine macrophage cells. The proposed studies represent a high potential for improving clinical strategies for treating environmentally-­related inflammation in a very cost-­effective and user-­friendly manner.

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