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.

项目摘要 动脉粥样硬化性心血管疾病（CVD）是全球死亡率和发病率的主要原因， 最近的大规模人体研究表明， （EDCs）和CVD。然而，暴露于内分泌干扰物和其他环境化学物质如何影响心血管疾病风险， 仍然知之甚少，并继续阻碍评估EDC暴露的健康风险。与 在NIEHS的资金支持下，我们已经确定了许多内分泌干扰物作为外源性生物素传感器的有效激动剂， 受体（PXR）。作为PXR配体的EDCs的鉴定为研究新的PXR受体提供了重要工具。 EDC暴露影响疾病的机制。我们的实验室是第一个揭示这部小说的 PXR在动脉粥样硬化发展中的调节作用，并且还证明了广泛使用的 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分泌干扰物增加动脉粥样硬化， 在各种小鼠模型中通过PXR信号传导抑制血脂异常。化学环境对 人类健康已经成为人们强烈关注的主题，但是在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，毒理学， 药理学和心血管研究使我处于一个独特的位置，以研究“基因-EDC 相互作用”影响动脉粥样硬化的发展和脂质体内平衡。这种EDC诱导的CVD 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 研究EDC暴露对脂质稳态和动脉粥样硬化影响的广泛科学主题 在成年人和他们的后代。EICVD-RIVER将解决以下具体的科学问题：1）有多少 塑料和其他消费品中的常见化学物质作为内分泌干扰物来调节PXR活性？可以 不同的EDC混合物协同激活PXR？2)内分泌干扰物通过哪些细胞特异性机制 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以影响EDC- 诱发动脉粥样硬化？4)微塑料对EDC诱导的动脉粥样硬化有特洛伊木马效应吗？ 它们能否使细胞内EDCs对PXR介导的动脉粥样硬化产生协同或叠加影响？第五章） 父亲暴露于PXR激动性内分泌干扰物是否影响后代动脉粥样硬化的发展？如何 PXR信号改变精子RNA编码增加后代CVD风险吗？拟议的研究将 有助于我们理解基因EDC相互作用的易感个体及其后代， CVD，我的专业知识和经验是一个理想的适合河流机制，支持多个， 长期研究的建议维度。