A novel mechanism for ART-associated dyslipidemia and atherosclerosis

ART 相关血脂异常和动脉粥样硬化的新机制

基本信息

批准号：
9273599
负责人：
Changcheng Zhou
金额：
$ 37.35万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9273599
关键词：
Adverse effects Agonist Amprenavir Animal Model Anti-Retroviral Agents Apolipoprotein E Arterial Fatty Streak Atherosclerosis Awareness CD36 gene Cardiovascular Diseases Cells Chemicals Cholesterol Chronic Clinical Comorbidity Development Diet Disease Dose Drug Regulations Dyslipidemias Foam Cells Follow-Up Studies Gene Expression Generations Goals HIV HIV Infections HIV Protease Inhibitors HIV therapy Health Heart Homeostasis Hyperlipidemia In Vitro Individual Infection Inflammation Intestines Knockout Mice Laboratories Lipids Liver Long-Term Survivors Longevity Lopinavir Mediating Modeling Molecular Morbidity - disease rate Mus Nuclear Receptors Pathway interactions Patients Pharmaceutical Preparations Pilot Projects Protease Inhibitor Receptor Activation Regulation Risk Ritonavir Role SXR receptor Signal Pathway Testing Therapeutic Uses Wild Type Mouse Xenobiotic Metabolism Xenobiotics absorption antiretroviral therapy atherogenesis base cardiovascular disorder risk cholesterol transporters defined contribution disorder risk drug metabolism efavirenz experimental study in vivo insight macrophage mortality mouse model non-nucleoside reverse transcriptase inhibitors novel pregnane X receptor public health relevance receptor function scavenger receptor sensor survivorship uptake

项目摘要

DESCRIPTION (provided by applicant): The rise in long-term HIV survivorship as a result of the introduction of effective antiretroviral therapy (ART) over the past decades has generated new awareness of the sequelae of both HIV infection and of the therapeutics used to treat HIV patients. Accumulating evidence of comorbidities associated with HIV infection and treatment with antiretroviral (ARV) drugs includes significant dyslipidemia and elevated risk of developing atherosclerotic cardiovascular disease (CVD). The goal of this project is to investigate a novel mechanism of ART-associated dyslipidemia and cardiovascular disease (CVD). Several ARV drugs have been identified as potent agonists for the pregnane X receptor (PXR), a nuclear receptor activated by numerous drugs, xenobiotic and dietary chemicals. PXR functions as a xenobiotic sensor that induces expression of genes required for xenobiotic metabolism in the liver and intestine. In the past decade, the function of PXR in the regulation of drug and xenobiotic metabolism has been extensively studied by many laboratories and the role of PXR as a xenobiotic sensor has been well established. We have recently revealed the pro-atherogenic effects of PXR in animal models and demonstrated that chronic PXR activation induces hyperlipidemia in wild-type mice and increases atherosclerosis in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice. Preliminary studies demonstrated that HIV protease inhibitor amprenavir activates PXR and induces hyperlipidemia in wild- type mice but not in PXR-deficient mice; furthermore, follow-up study of currently used first-line ARV drugs subsequently found that these drugs activated PXR and induced PXR-mediated gene expression. The goal of this project is to generate novel mechanistic insights into ART-associated dyslipidemia and risk of CVD. Our central hypothesis is that long-term treatment with ARV drugs that activate PXR will lead to aberrant lipid homeostasis and accelerated atherosclerosis. We propose the following specific aims to test this hypothesis: 1) Determine the contribution of PXR towards the adverse effects of currently recommended ARV drugs on lipid homeostasis; 2) Define the molecular mechanisms through which PXR agonistic ARV drugs induce hyperlipidemia; and 3) Determine the impact of ARV drug-mediated PXR activation on macrophage functions and atherosclerosis development. These studies will provide critical mechanistic insights and new understandings of ART-associated dyslipidemia and CVD risk and will have direct clinical consequences for patients undergoing long-term treatment with PXR agonistic drugs.

描述（由适用提供）：由于引入有效的抗逆转录病毒疗法（ART），长期HIV生存期的上升在过去几十年中引起了人们对HIV感染和治疗HIV患者的疗法的新认识。与HIV感染和用抗逆转录病毒（ARV）药物治疗有关的合并症的累积证据包括严重的血脂异常和患有动脉粥样硬化心血管疾病（CVD）的风险升高。该项目的目的是研究一种新型的与艺术相关血脂异常和心血管疾病（CVD）的机制。几种ARV药物已被鉴定为怀孕X受体（PXR）的潜在激动剂，这是一种由许多药物，异种生物和饮食化学物质激活的核受体。 PXR充当一种诱导异种生物所需基因表达的异生物传感器。肝脏和肠中的代谢。在过去的十年中，PXR在药物和异种代谢的调节中的功能已被许多实验室广泛研究，并且PXR作为异生元传感器的作用已得到很好的确定。我们最近揭示了PXR在动物模型中的促动源性作用，并证明慢性PXR激活诱导野生型小鼠中的高脂血症，并增加动脉粥样硬化的apolipopprotein e-Deceprotein e-缺陷型（APOE-/ - ）小鼠的动脉粥样硬化。初步研究表明，HIV蛋白酶抑制剂Amprenavir激活野生型小鼠的PXR和诱导的高脂血症，但在PXR缺陷型小鼠中却没有激活PXR。此外，对当前使用的一线ARV药物的后续研究随后发现这些药物激活了PXR并诱导PXR介导的基因表达。该项目的目的是对与艺术相关的血脂异常和CVD风险产生新的机械见解。我们的中心假设是激活PXR的ARV药物的长期治疗将导致异常的脂质稳态并加速动脉粥样硬化。我们提出以下具体旨在检验这一假设的特定目的：1）确定PXR对当前推荐的ARV药物对脂质稳态的不利影响的贡献； 2）定义PXR激动剂ARV药物诱导高脂血症的分子机制； 3）确定ARV药物介导的PXR激活对巨噬细胞功能和动脉粥样硬化发展的影响。这些研究将提供关键的机械见解和对艺术相关血脂异常和CVD风险的新理解，并将对接受PXR激动药长期治疗的患者产生直接的临床后果。