Role of PXR in EDC-induced cardiovascular disease

PXR 在 EDC 诱发的心血管疾病中的作用

• 批准号: 10640665
• 负责人: Changcheng Zhou
• 金额: $ 84.93万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-05 至 2031-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640665
• 关键词: Adult; Affect; Agonist; Atherosclerosis; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Ceramides; Chemical Exposure; Chemicals; Chronic; Citrates; Code; Development; Dimensions; Disease; Dyslipidemias; Endocrine Disruptors; Environment; Environmental Health; Equus caballus; Etiology; Exposure to; Funding; Genes; Health; Homeostasis; Human; Individual; Laboratories; Ligands; Link; Lipids; Longitudinal Studies; Mediating; Molecular Biology; Morbidity - disease rate; National Institute of Environmental Health Sciences; Paternal Exposure; Pharmacology; Plastics; Positioning Attribute; RNA; Receptor Signaling; Regulation; Research; Risk Assessment; Role; Toxicology; Training; Xenobiotics; bisphenol A; cardiovascular disorder risk; chemical association; consumer product; environmental chemical; experience; health assessment; human disease; innovation; interest; intergenerational; mortality; mouse model; new therapeutic target; novel; offspring; phthalates; pregnane X receptor; programs; sensor; sperm cell; tool

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.

项目概要 动脉粥样硬化性心血管疾病（CVD）是全世界死亡和发病的主要原因 最近的大规模人体研究表明，接触内分泌干扰化学物质之间存在联系 （EDC）和CVD。然而，接触 EDC 和其他环境化学物质如何影响 CVD 风险尚不清楚。 仍然知之甚少，并且继续阻碍对 EDC 暴露的健康风险的评估。随着 在 NIEHS 的资助下，我们已经确定许多 EDC 是外源传感器孕烷 X 的有效激动剂 受体（PXR）。 EDCs作为PXR配体的鉴定为新的研究提供了重要工具 EDC 暴露影响疾病的机制。我们的实验室是第一个揭露这部小说的 PXR 在调节动脉粥样硬化发展中的功能，并且还证明了广泛使用的 EDC 包括双酚 A、邻苯二甲酸二环己酯和柠檬酸三丁酯，会增加动脉粥样硬化和 在各种小鼠模型中通过 PXR 信号传导导致血脂异常。化学环境对 人类健康已成为人们强烈关注的主题，但 EDC 研究领域的研究很少 重点关注动脉粥样硬化的发展。我在分子生物学、毒理学、 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”如何 “相互作用”会影响动脉粥样硬化的发展和脂质稳态。这种 EDC 诱导的 CVD 革命性创新、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 在成年人及其后代中。 EICVD-RIVER 将解决以下具体科学问题：1）有多少 塑料和其他消费品中的常见化学物质可以充当 EDC 来调节 PXR 活动吗？能 不同的 EDC 混合物可以协同激活 PXR？ 2) EDC通过哪些细胞特异性机制发挥作用 诱发血脂异常和动脉粥样硬化？ 3）PXR如何调节神经酰胺稳态来影响EDC- 诱发动脉粥样硬化？ 4）微塑料对EDC引起的动脉粥样硬化有特洛伊木马效应吗？ 它们能否将 EDC 引入细胞内，对 PXR 介导的动脉粥样硬化产生协同或附加影响？ 5） 父亲接触 PXR 激动性 EDC 是否会影响后代动脉粥样硬化的发展？如何 PXR 信号传导是否会改变精子 RNA 代码以增加后代的 CVD 风险？拟议的研究将 有助于我们理解基因-EDC 相互作用在个体及其后代中的易感性 CVD 以及我的专业知识和经验非常适合支持多方合作的 RIVER 机制 拟议研究的维长期研究。