Role of PXR in drug-elicited cardiovascular disease

PXR 在药物引起的心血管疾病中的作用

基本信息

批准号：
10576675
负责人：
Hong Chen
金额：
$ 72.59万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576675
关键词：
Ablation Adverse effects Affect Agonist Animal Model Antipsychotic Agents Atherosclerosis Attenuated Bipolar Disorder Blood Circulation Cardiovascular Diseases Cause of Death Chronic Clinical Development Dietary Fats Drug Interactions Drug usage Dyslipidemias Enterocytes Etiology Exposure to Genes Genetically Modified Animals Health Hepatic Homeostasis Human Hyperlipidemia Immunofluorescence Immunologic In Vitro Intercellular Junctions Intestinal Absorption Intestines KDR gene Knockout Mice Knowledge Life Style Ligands Lipids Lymphatic Lymphatic Endothelial Cells Lymphatic System Lymphocyte Major Depressive Disorder Mediating Methods Molecular Morbidity - disease rate Mus Nuclear Receptors Patients Pharmaceutical Preparations Phytochemical Pilot Projects Population Property Proteomics Psychiatric therapeutic procedure Receptor Activation Receptor Signaling Regulation Risk Role Schizophrenia Signal Transduction Stains Sulforaphane Testing Therapeutic Tissues Transmission Electron Microscopy Vascular Endothelial Growth Factor Receptor-3 Work Xenobiotic Metabolism Xenobiotics absorption antagonist atherogenesis atypical antipsychotic cardiovascular disorder risk clinically relevant driving force drug development experimental study humanized mouse in vivo innovation insight lacteal lipid metabolism lymphatic vessel mortality mouse model novel novel strategies pharmacologic pregnane X receptor prevent quetiapine receptor receptor function sensor single-cell RNA sequencing uptake

项目摘要

Project Summary Antipsychotic therapy is widely used in the treatment of psychiatric conditions including bipolar disorder, schizophrenia, and major depressive disorder. These conditions, which together affect more than 20% of the population, usually require lifelong medication. Atypical antipsychotics have superior therapeutic action and reduced adverse effects as compared with typical antipsychotics, but the use of atypical antipsychotics is also associated with dyslipidemia and an increased risk of cardiovascular disease (CVD) in patients. The underlying mechanisms responsible for these adverse effects remain largely unknown, which poses serious health challenges to patients undergoing long-term antipsychotic treatment. To this end, we recently identified several atypical antipsychotics including quetiapine that promote dyslipidemia, as potent agonists for the nuclear receptor pregnane X receptor (PXR). Our previous work revealed novel and unsuspected roles of PXR in lipid homeostasis and atherogenesis, and showed that PXR ligands increase dyslipidemia and atherosclerosis in atherogenic mouse models including PXR-humanized mice. Given intestine and lymphatic systems are essential for dietary lipid absorption and transport, our latest preliminary study using novel tissue-specific PXR knockout mouse models demonstrated that exposure to quetiapine fails to cause hyperlipidemia in intestine- specific PXR knockout mice. How PXR signaling in enterocytes regulates the intestinal lipid metabolism is an open and highly clinically relevant question. Furthermore, our pilot study revealed that ablation of PXR blunts VEGF receptor 3 signaling in lymphatic endothelial cells and reduces lymphatic button junction formation in lacteals of PXR-deficient mice. It is completely unknow how lymphatic PXR regulates lipid absorption and transport by gut lymphatic vessels. To unveil the aforementioned central mystery and to study the action mode of PXR in mediating antipsychotic-elicited adverse effects on lipid homeostasis and atherosclerosis, we propose the following specific aims to determine the molecular mechanisms of the atherogenic effects of atypical antipsychotics: 1) Define the enterocyte signaling through which PXR-activating antipsychotics regulate lipid homeostasis and atherosclerosis; 2) Determine the molecular mechanisms underlying PXR- regulated lymphatic lipid absorption and transport in atherosclerosis; and 3) Investigate the therapeutic potential of a naturally occurring PXR antagonist in preventing antipsychotic-induced dyslipidemia and atherosclerosis. Successful completion of the proposed work will fill in the void in uncovering novel molecular mechanisms underlying antipsychotic therapy-associated CVD risk. Our findings may also inaugurate new class of therapeutic strategies to treat dyslipidemia in patients undergoing long-term antipsychotic therapy.

项目概要抗精神病药物广泛用于治疗精神疾病，包括双相情感障碍、精神分裂症和重度抑郁症。这些条件加在一起影响了 20% 以上人群，通常需要终身服药。非典型抗精神病药具有优越的治疗作用与典型抗精神病药物相比，不良反应减少，但使用非典型抗精神病药物也与血脂异常和患者心血管疾病（CVD）风险增加有关。底层的造成这些不良影响的机制仍然很大程度上未知，这对健康造成严重影响长期接受抗精神病药物治疗的患者面临挑战。为此，我们最近确定了几非典型抗精神病药，包括促进血脂异常的喹硫平，作为核细胞的有效激动剂受体孕烷X受体(PXR)。我们之前的工作揭示了 PXR 在脂质中的新颖且意想不到的作用体内平衡和动脉粥样硬化，并表明 PXR 配体会增加血脂异常和动脉粥样硬化致动脉粥样硬化小鼠模型，包括 PXR 人源化小鼠。鉴于肠道和淋巴系统是对于膳食脂质吸收和运输至关重要，我们使用新型组织特异性 PXR 进行的最新初步研究基因敲除小鼠模型表明，暴露于喹硫平不会引起肠道高脂血症特定 PXR 基因敲除小鼠。肠上皮细胞中的 PXR 信号如何调节肠道脂质代谢是一个研究领域开放且与临床高度相关的问题。此外，我们的初步研究表明，消融 PXR 会减弱淋巴内皮细胞中的 VEGF 受体 3 信号传导并减少淋巴纽扣连接的形成 PXR 缺陷小鼠的乳糜管。目前完全不知道淋巴PXR如何调节脂质吸收和通过肠道淋巴管运输。揭开前述核心谜团并研究其行动模式 PXR 在介导抗精神病药物引起的脂质稳态和动脉粥样硬化不良反应中的作用，我们提出以下具体目标来确定动脉粥样硬化效应的分子机制非典型抗精神病药：1) 定义 PXR 激活抗精神病药所通过的肠上皮细胞信号传导调节脂质稳态和动脉粥样硬化； 2) 确定PXR-的分子机制调节动脉粥样硬化中淋巴脂质的吸收和运输； 3) 研究治疗方法天然存在的 PXR 拮抗剂在预防抗精神病药引起的血脂异常方面的潜力动脉粥样硬化。拟议工作的成功完成将填补发现新分子的空白抗精神病治疗相关 CVD 风险的潜在机制。我们的发现也可能开启新的治疗长期抗精神病药物治疗患者血脂异常的一类治疗策略。