Role of PXR in EDC-induced cardiovascular disease

项目摘要 动脉粥样硬化性心血管疾病(CVD)是世界范围内导致死亡和发病率的主要原因 最近的大规模人体研究表明，接触内分泌干扰性化学物质 (EDCS)和CVD。然而，暴露于EDCs和其他环境化学品对心血管疾病风险的影响是 仍然知之甚少，并继续阻碍对EDC暴露的健康风险的评估。与 NIEHS的资金支持，我们已经确定许多内皮细胞是外源生物传感器孕烷X的有效激动剂 受体(PXR)。内分泌细胞作为PXR配体的鉴定为新的研究提供了重要的工具 EDC暴露影响疾病的机制。我们实验室率先揭开了这本小说的面纱 PXR在调节动脉粥样硬化发展中的作用也已显示出广泛的用途 包括双酚A、邻苯二甲酸二环己酯和柠檬酸三丁酯在内的内皮细胞可增加动脉粥样硬化和 在不同的小鼠模型中通过PXR信号转导的血脂异常。化学环境对环境的影响 人类健康已经成为人们高度感兴趣的主题，但在EDC研究领域中很少有研究 专注于动脉粥样硬化的发展。我在分子生物学，毒物学， 药理学和心血管研究使我处于一个独特的位置来研究“基因-EDC 相互作用“影响动脉粥样硬化的发展和脂质的动态平衡。这种EDC诱导的心血管疾病 革命性的创新、有远见的环境健康研究计划(EICVD-River)将使我能够 调查EDC暴露对脂质稳态和动脉粥样硬化影响的广泛科学主题 在成年和他们的后代身上。EICVD-River将解决以下具体的科学问题：1)多少 塑料和其他消费品中的常见化学物质作为内皮细胞调节PXR活动？能 不同的EDC混合物协同激活PXR？2)通过什么细胞特异性机制使EDC 诱导血脂异常和动脉粥样硬化？3)PXR如何调节神经酰胺稳态影响EDC- 诱导动脉粥样硬化？4)微塑料在EDC诱导的动脉粥样硬化中有特洛伊木马效应吗？ 它们能否使细胞内的内皮细胞对PXR介导的动脉粥样硬化产生协同或相加的影响？5) 父亲暴露于PXR激动型内皮细胞是否会影响子代动脉粥样硬化的发展？多么 PXR信号是否会改变精子的RNA编码，从而增加后代患心血管疾病的风险？拟议的研究将 有助于我们理解基因-EDC相互作用使个体及其后代易患 CVD，以及我的专业知识和经验非常适合支持多个 提出长期维度研究的建议研究。

Project Summary Atherosclerotic cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide and recent large-scale human studies have implicated a link between exposure to endocrine disrupting chemicals (EDCs) and CVD. However, how exposure to EDCs and other environmental chemicals influences CVD risk is still poorly understood, and continues to hamper assessment of the health risks of EDC exposure. With the NIEHS funding support, we have identified many EDCs as potent agonists of the xenobiotic sensor pregnane X receptor (PXR). The identification of EDCs as PXR ligands has provided an important tool for the study of new mechanisms through which EDC exposure impacts disease. Our laboratory was the first to reveal the novel function of PXR in the regulation of atherosclerosis development, and has also demonstrated that widely-used EDCs including bisphenol A, dicyclohexyl phthalate, and tributyl citrate increase atherosclerosis and dyslipidemia through PXR signaling in various mouse models. Influences of the chemical environment on human health have become the subject of intense interest but very few studies in the EDC research field have focused on atherosclerosis development. My diverse scientific training in molecular biology, toxicology, pharmacology, and cardiovascular research has put me in a unique position to investigate how “gene-EDC interactions” affect atherosclerosis development and lipid homeostasis. This EDC-Induced CVD Revolutionizing Innovative, Visionary Environmental health Research Program (EICVD-RIVER) will allow me to investigate the broad scientific theme of the impact of EDC exposure on lipid homeostasis and atherosclerosis in adults and their offspring. EICVD-RIVER will address the following specific scientific questions: 1) How many common chemicals in plastic and other consumer products act as EDCs to modulate PXR activities? Can different EDC mixtures synergistically activate PXR? 2) Through which cell-specific mechanisms do EDCs induce dyslipidemia and atherosclerosis? 3) How does PXR regulate ceramide homeostasis to affect EDC- induced atherosclerosis? 4) Do microplastics have a Trojan Horse effect on EDC-induced atherosclerosis? Can they bring EDCs intracellularly to have synergistic or additive impact on PXR-mediated atherosclerosis? 5) Does paternal exposure to PXR agonistic EDCs affect the atherosclerosis development of the offspring? How does PXR signaling alter the sperm RNA code to increase CVD risk of the offspring? The proposed studies will contribute to our understanding of gene-EDC interactions in predisposing individuals and their offspring to CVD, and my expertise and experience are an ideal fit for the RIVER mechanism that supports a multi- dimensional long-term study of the proposed research.