Role of PXR in drug-elicited cardiovascular disease

PXR 在药物引起的心血管疾病中的作用

• 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
• 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

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.

项目摘要 抗精神病药疗法广泛用于治疗精神病病，包括躁郁症， 精神分裂症和重度抑郁症。这些条件共同影响超过20％的条件 人口通常需要终身药物。非典型抗精神病药具有卓越的治疗作用，并且 与典型抗精神病药相比，不良反应减少了，但非典型抗精神病药的使用也是 与血脂异常有关，患者患心血管疾病（CVD）的风险增加。基础 造成这些不良影响的机制仍然很大未知，这会带来严重的健康 对接受长期抗精神病药物治疗的患者面临挑战。为此，我们最近确定了几个 非典型抗精神病药，包括促进血脂异常的喹硫平，作为核的有效激动剂 受体妊娠X受体（PXR）。我们以前的作品揭示了PXR在脂质中的新颖和无引起的作用 稳态和动脉粥样硬化，并表明PXR配体增加了血脂异常和动脉粥样硬化 动脉粥样硬化小鼠模型，包括PXR人性化小鼠。给定肠和淋巴系统是 对于饮食脂质吸收和运输至关重要，我们使用新型组织特异性PXR的最新初步研究 敲除小鼠模型表明，暴露于喹硫平的暴露不会引起肠道高脂血症。 特定的PXR敲除小鼠。肠上皮细胞中的PXR信号如何调节肠脂质代谢是一种 开放且高度临床相关的问题。此外，我们的试点研究表明，PXR的消融是钝的 VEGF受体3淋巴内皮细胞中的信号传导并减少淋巴纽扣连接形成 PXR缺陷小鼠的乳酸。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。揭示上述中央谜团并研究动作模式 PXR在介导抗精神病药物对脂质稳态和动脉粥样硬化的不良反应中，我们 提出以下特定旨在确定动脉粥样硬化作用的分子机制 非典型抗精神病药：1）定义肠球菌信号传导，PXR激活抗精神病药 调节脂质稳态和动脉粥样硬化； 2）确定PXR-的分子机制 调节动脉粥样硬化的淋巴脂质吸收和转运； 3）研究治疗 天然存在的PXR拮抗剂在防止抗精神病药引起的血脂异常和 动脉粥样硬化。拟议工作的成功完成将填充在揭示新的分子的空隙中 抗精神病药疗法相关的CVD风险的机制。我们的发现也可能成立新的 治疗长期抗精神病药疗法患者血脂异常的治疗策略类别。