HIV Protease Inhibitors, the Unfolded Protein Response and Atherosclerosis

HIV 蛋白酶抑制剂、未折叠蛋白反应和动脉粥样硬化

基本信息

批准号：
7268024
负责人：
HUIPING Rose ZHOU
金额：
$ 21.7万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7268024
关键词：
Accounting Acquired Immunodeficiency Syndrome Adult Adverse effects Aftercare Animal Model Anti-Retroviral Agents Apoptosis Apoptotic Arterial Fatty Streak Atazanavir Atherosclerosis C57BL/6 Mouse Calcium Cardiovascular Diseases Cessation of life Child Cholesterol Clinical Condition Data Development Diabetes Mellitus Disease Dyslipidemias Endoplasmic Reticulum Environment Epidemic Esterification Event Functional disorder HIV Highly Active Antiretroviral Therapy Homeostasis Human Hyperhomocysteinemia Indinavir Inflammatory Lesion Life Link Lipids Longevity Metabolic Metabolic syndrome Molecular Morbidity - disease rate Numbers Patients Pattern Phase Play Process Protease Inhibitor Protein Glycosylation Proteins Reporting Research Personnel Risk Factors Ritonavir Role Rupture Signal Pathway Signal Transduction Pathway Specimen Stress Testing Thrombus United States Update Viral Virus Diseases World Health Organization base cell growth cell type coping in vivo macrophage mortality mouse model novel novel therapeutics programs protein misfolding response

项目摘要

DESCRIPTION (provided by applicant): HIV protease inhibitors have been successfully used in highly active anti-retroviral therapy (HAART) for HIV infection. Incorporation of protease inhibitors in HAART causes profound and sustained suppression of viral replication, significantly reduces the morbidity and mortality, and prolongs the lifespan of patients with HIV infection. Unfortunately, the benefits of HIV protease inhibitors are compromised by a number of metabolic abnormalities. One of the most deleterious side effects of HIV protease inhibitor therapy is the development of dyslipidemia, which is a well established risk factor for the development of atherosclerosis. However, the exact mechanisms by which HIV protease inhibitors promote atherosclerosis remain unclear. Macrophages are the most prominent cell type involved in atherosclerotic lesions and play key roles in all phases of atherosclerosis. A portion of macrophages become apoptotic, particularly in advanced lesions, which is regulated or controlled by numerous factors. One critical step for inducing macrophage apoptosis is to disrupt endoplasmic reticulum (ER) homeostasis, thus triggering the ER stress signal transduction pathway, known as the unfolded protein response (UPR). UPR plays a critical role in regulating cell growth, differentiation, and apoptosis. Importantly, the UPR has been linked to macrophage apoptosis in atherosclerotic lesions. Our preliminarily data demonstrate that treatment with HIV protease inhibitors increases the accumulation of intracellular free cholesterol, activates the UPR, and induces apoptosis in macrophages. Based on these novel findings, we HYPOTHESIZE that HIV protease inhibitors promote atherosclerosis by disrupting lipid homeostasis, activating the UPR, and inducing apoptosis in macrophages. Three specific aims are proposed to test the hypothesis. Aim#1: To determine the effects of clinically used HIV protease inhibitors on UPR activation both in cultured macrophages and in vivo. Aim#2: To elucidate the cellular/molecular mechanisms leading to UPR activation by HIV protease inhibitors in macrophages. Aim#3: To determine whether HIV protease inhibitor-induced UPR activation is responsible for the formation of atherosclerotic lesions in vivo mouse models. Completion of these specific aims will help identify and establish new cellular/molecular mechanisms of HIV protease inhibitor-induced atherosclerosis, thereby enhancing our understanding of the mechanisms of HAART-associated cardiovascular diseases and providing novel information for the development of new therapeutic strategies.

描述（由申请人提供）：HIV蛋白酶抑制剂已成功用于高度活跃的抗逆转录病毒疗法（HAART）用于HIV感染。在HAART中掺入蛋白酶抑制剂会导致病毒复制的深刻和持续抑制，从而显着降低发病率和死亡率，并延长HIV感染患者的寿命。不幸的是，艾滋病毒蛋白酶抑制剂的益处受到许多代谢异常的损害。 HIV蛋白酶抑制剂疗法最有害的副作用之一是血脂异常的发展，这是动脉粥样硬化发展的良好危险因素。然而，HIV蛋白酶抑制剂促进动脉粥样硬化的确切机制尚不清楚。巨噬细胞是涉及动脉粥样硬化病变的最突出的细胞类型，并在动脉粥样硬化的所有阶段中起关键作用。一部分巨噬细胞成为凋亡，尤其是在晚期病变中，该病变受许多因素调节或控制。诱导巨噬细胞凋亡的一个关键步骤是破坏内质网（ER）稳态，从而触发ER应力信号转导途径，称为展开的蛋白质反应（UPR）。 UPR在调节细胞生长，分化和凋亡中起着至关重要的作用。重要的是，UPR与动脉粥样硬化病变中的巨噬细胞凋亡有关。我们的初步数据表明，用HIV蛋白酶抑制剂的治疗增加了细胞内游离胆固醇的积累，激活UPR并诱导巨噬细胞凋亡。基于这些新的发现，我们假设HIV蛋白酶抑制剂通过破坏脂质稳态，激活UPR并诱导巨噬细胞凋亡来促进动脉粥样硬化。提出了三个特定目标来检验该假设。 AIM＃1：确定临床使用的HIV蛋白酶抑制剂对培养的巨噬细胞和体内UPR激活的影响。目标＃2：阐明导致巨噬细胞中HIV蛋白酶抑制剂UPR激活的细胞/分子机制。 AIM＃3：确定HIV蛋白酶抑制剂诱导的UPR激活是否导致体内小鼠模型中动脉粥样硬化病变的形成。这些特定目标的完成将有助于识别并建立新的细胞/分子机制的HIV蛋白酶抑制剂引起的动脉粥样硬化，从而增强我们对HAART相关心血管疾病机制的理解，并为开发新的治疗策略的发展提供新的信息。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The cellular pharmacokinetics of HIV protease inhibitors: current knowledge and future perspectives.

DOI：
10.2174/138920012802850119
发表时间：
2012-09
期刊：
Current drug metabolism
影响因子：
2.3
作者：
Wei-bin Zha;B. Zha;F. Zhou;Huiping Zhou;Guangji Wang
通讯作者：
Wei-bin Zha;B. Zha;F. Zhou;Huiping Zhou;Guangji Wang

Anti-Inflammatory and antiproliferative activities of trifolirhizin, a flavonoid from Sophora flavescens roots.

DOI：
10.1021/jf900340b
发表时间：
2009-06-10
期刊：
Journal of agricultural and food chemistry
影响因子：
6.1
作者：
Zhou H;Lutterodt H;Cheng Z;Yu LL
通讯作者：
Yu LL

Cholesterol rich lipid raft microdomains are gateway for acute phase protein, SERPINA1.

富含胆固醇的脂筏微结构域是急性期蛋白 SERPINA1 的门户。

DOI：
10.1016/j.biocel.2010.06.009
发表时间：
2010
期刊：
The international journal of biochemistry & cell biology
影响因子：
0
作者：
Subramaniyam,Devipriya;Zhou,Huiping;Liang,Min;Welte,Tobias;Mahadeva,Ravi;Janciauskiene,Sabina
通讯作者：
Janciauskiene,Sabina

Development of a novel self-microemulsifying drug delivery system for reducing HIV protease inhibitor-induced intestinal epithelial barrier dysfunction.