Project 2 - Molecular and Cellular Mechanisms of Cardiometabolic Toxicity of VOCs

摘要 接触毒物与慢性疾病的发展或恶化有关。然而，几乎没有什么是 已知挥发性有机化合物(VOC)-一类有毒物质-与较高的 2型糖尿病(T2D)和中风--促进心脏代谢疾病(CMD)的发展。因此， 这个超级基金项目的总体目标是确定VOCs负面影响的机制 影响心血管健康和代谢，确定VOC暴露和血管损伤的生物标志物，以及 测试治疗策略，以最大限度地减少VOC诱导的CMD。我们在当前资金周期的研究和 初步数据表明，苯、氯乙烯和巴豆醛等VOC促进内质 网状蛋白(ER)应激并触发内皮细胞的未折叠蛋白反应(UPR)。具体来说，我们 假设VOC的醛代谢物，通常比它们的母体化合物毒性更大， 通过诱导内质网应激来降低内皮毒性，内质网应激触发代谢变化，加速异位脂肪 沉积并促进心脏代谢功能障碍。为了验证这一假设，我们将：(1)检查以下因素的影响 VOC暴露对内皮细胞功能和胰岛素抵抗的影响；(2)描述蛋白质错误折叠的贡献 VOC的心脏代谢毒性。这些研究的设计包括分子和药理学。 旨在解毒或熄灭VOC暴露引起的活性中间体的干预措施以及 可能导致识别VOC暴露和VOC暴露的新的、敏感的和强大的生物标志物的研究 血管损伤。这些研究的目的是协同作用，并提供生物学上的可信 项目1中确定的协会。该项目的成功完成将导致确定 VOC影响心脏代谢功能并提供 对如何通过靶向醛或蛋白质来预防或在治疗上将VOC毒性降至最低的见解- 折叠的小路。

SUMMARY Exposure to toxicants has been linked to the development or exacerbation of chronic disease. However, little is known about how volatile organic chemicals (VOC)—a class of toxicants associated with higher prevalence of type 2 diabetes (T2D) and stroke—promote the development of cardiometabolic disease (CMD). Accordingly, the overarching goals of this Superfund project are to determine the mechanisms by which VOCs negatively impact cardiovascular health and metabolism, identify biomarkers for VOC exposure and vascular injury, and test therapeutic strategies to minimize VOC-induced CMD. Our studies in the current funding cycle and preliminary data suggest that VOC such as benzene, vinyl chloride, and crotonaldehyde promote endoplasmic reticulum (ER) stress and trigger the unfolded protein response (UPR) in endothelial cells. Specifically, we hypothesize that aldehyde metabolites of VOC, which are generally more toxic than their parent compound, diminish endothelial toxicity by inducing ER stress, which triggers metabolic changes that accelerate ectopic lipid deposition and promote cardiometabolic dysfunction. To test this hypothesis we will: (1) examine the effects of VOC exposure on endothelial function and insulin resistance; (2) delineate the contribution of protein misfolding to the cardiometabolic toxicity of VOC. The design of these studies includes molecular and pharmacological interventions designed to detoxify or quench the reactive intermediates evoked by VOC exposure as well as studies that could lead to the identification of novel, sensitive and robust biomarkers of both VOC exposure and vascular injury. These studies were designed to synergize with and provide biological plausibility for the associations identified in Project 1. Successful completion of this project will lead to identification of the underlying cellular and molecular mechanisms by which VOC affect cardiometabolic function and provide insights into how VOC toxicity could be prevented or therapeutically minimized by targeting aldehydes or protein- folding pathways.