Project 2 - Effects of Particulate Matter on Insulin Resistance and Endothelial

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Inhalation of fine particulate matter air (PM) pollution (<2.5pm) is associated with an increased risk for cardiovascular disease (CVD) and Type 2 diabetes (T2D). Short-term exposure of mice to concentrated ambient air particulate matter (CAP) decreases vascular insulin sensivity and circulating endothelial progenitor cells (EPCs). EPCs are thought to be involved in endothelial maintenance, thus we propose that CAP-induced suppression of circulating and tissue-resident EPCs leads to endothelial injury and insulin resistance, which provokes systemic insulin resistance ultimatively increasing the risk for T2D and CVD. CAP exposure affects vascular health by triggering low-grade inflammation via Inflammasome activation. To elucidate both, mechanism(s) and causal relationship of endothelial injury, EPC depletion and vascular insulin resistance we will examine in the aim 1:1) whether CAP-exposure alone is sufficient to induce systemic insulin resistance or whether it only exacerbates the effects of obesity, and 2) the physico-chemical composition and body deposition of CAP to establish a more precise dosimetry and to find potential particle properties responsible for the biological effects. In our second aim we will investigate whether alterations in circulating/tissue resident EPCs and endothelial health are causative for the development of vascular insulin resistance. Finally, to find the mechanisms of CAP-induced vascular insulin resistance we will examine in aim 3 a possible role ofthe activation ofthe inflammasome. We will utilize a mouse model of diet-induced obesity (DIO) to investigate effects of HFD-feeding, and use mice deficient in NLRP3 and Casp-1 to test the contribution of Inflammasome activation in the development of vascular insulin resistance. Completion of these studies will provide novel insights into the mechanism(s) by which inhaled ambient particles increase the risk for T2D and CVD, and as such will provide unique and detailed information of particle dose, composition and deposition and their correlation with biological responses, which could lead to the development of novel biomarkers and strategies for the regulation of environmental pollutants and the prevention and management of insulin resistance, obesity, T2D and CVD.