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

吸入细颗粒物空气（PM）污染（<2.5pm）与心血管疾病（CVD）和2型糖尿病（T2 D）的风险增加有关。小鼠短期暴露于浓缩的环境空气颗粒物（CAP）会降低血管胰岛素敏感性和循环内皮祖细胞（EPCs）。EPCs被认为参与内皮的维持，因此我们提出CAP诱导的循环和组织驻留EPCs的抑制导致内皮损伤和胰岛素抵抗，这引起全身胰岛素抵抗，最终增加T2 D和CVD的风险。CAP暴露通过炎症体激活触发低度炎症来影响血管健康。为了阐明内皮损伤、EPC耗竭和血管胰岛素抵抗的机制和因果关系，我们将在目标1中检查：1）单独的CAP暴露是否足以诱导全身胰岛素抵抗或是否仅加剧肥胖的影响，和2）CAP的物理化学组成和身体沉积，以建立更精确的剂量测定法并发现负责生物效应的潜在颗粒特性。在我们的第二个目标中，我们将研究循环/组织驻留EPCs和内皮健康的改变是否是血管胰岛素抵抗发展的原因。最后，为了找到CAP诱导的血管胰岛素抵抗的机制，我们将在目的3中研究炎性体激活的可能作用。我们将利用饮食诱导的肥胖（DIO）小鼠模型来研究HFD喂养的影响，并使用NLRP 3和Casp-1缺陷的小鼠来测试炎性小体激活在血管胰岛素抵抗发展中的作用。这些研究的完成将为吸入环境颗粒增加T2 D和CVD风险的机制提供新的见解，因此将提供颗粒剂量、组成和沉积及其与生物反应的相关性的独特和详细信息，这可能导致开发新的生物标志物和策略，用于调节环境污染物以及预防和管理胰岛素抵抗、肥胖、T2 D和CVD。

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.