HIV-Nef protein and endothelial dysfunction

HIV-Nef 蛋白与内皮功能障碍

基本信息

批准号：
9268569
负责人：
Matthias Clauss
金额：
$ 44.52万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2015-07-06 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9268569
关键词：
Acquired Immunodeficiency Syndrome Actins Address Adverse effects Aging Anti-Retroviral Agents Antibodies Antioxidants Antiviral Therapy Apolipoprotein E Apoptosis Atherosclerosis Biology Blood Cells Blood Vessels Blood flow Breeding CD4 Positive T Lymphocytes Cardiovascular Diseases Cardiovascular Pathology Cardiovascular system Cell Death Cell Line Cells Clinical Clinical Research Coronary Coronary artery Data Disease Endothelial Cells Endothelium Enzyme-Linked Immunosorbent Assay Event Fibrinogen Functional disorder Generations Goals HIV HIV Infections HIV Seropositivity Human In Vitro Individual Injectable Intervention Kidney Lead Link Liquid substance Lymph Mediating Mediator of activation protein Mitochondria Modeling Molecular Morbidity - disease rate Mus NADP NADPH Oxidase Nanotubes Pathogenesis Pathology Pathway interactions Patients Peripheral Blood Mononuclear Cell Play Polymers Population Pre-Clinical Model Process Production Proteins Publishing RNA Reactive Oxygen Species Risk Factors Role SH3 Domains Signal Transduction Structure System T-Lymphocyte Testing Time Tissues Transfer Factor Transgenic Mice Ursidae Family Validation Vascular Diseases Vascular Endothelial Cell Vascular Endothelium Viral Viremia Virus Virus Replication Work base cardiovascular risk factor disorder risk endothelial dysfunction heart cell improved in vivo in vivo Model inhibitor/antagonist insight intravital microscopy mitochondrial dysfunction mortality novel polymerization pre-clinical prevent promoter public health relevance tissue culture

项目摘要

DESCRIPTION (provided by applicant): Antiviral therapy is effective in preventing AIDS in HIV-infected people. However, an increasing number of HIV infected individuals suffer or even die of diseases other than AIDS including cardiovascular diseases. The biology behind these clinical observations is not well understood, although both anti-retroviral therapy (ART) dependent and independent mechanisms appear to be involved. Here we plan to study a key mechanism by which HIV can cause endothelial activation and dysfunction, which are believed to precede atherosclerotic processes. Nef is known to play a pivotal role in HIV pathogenesis and to mediate its own transfer from T cells to bystander cells. Therefore, we postulate that HIV-Nef can efficiently be transferred from T cells to other blood cells including vascular endothelial cells, which are in steady contact with flowing blood and lymph fluid. Indeed, we can show that transfer of Nef leads to endothelial cell activation and cell death, which can be effectively abrogated by NADPH oxidase inhibitors and antioxidants. Based on our published data that HIV dependent endothelial activation can be explained by transfer of Nef from blood cells to coronary arterial endothelial cells, we further hypothesize that transfer of Nef to vascular cells may lead to cardiovascular dysfunction and pathology of the cardiovascular system. We plan to address in preclinical in vitro and in vivo models the mechanism of Nef transfer to and activity in endothelial cells. We expect that identifying such targets will enable clinical interventions studis with appropriate inhibitors. Thus, determining the cellular mechanism of Nef-induced vascular pathology in vascular endothelial cells can help to identify HIV-Nef as a novel target for preventing and treating HIV- associated diseases.

描述（由申请人提供）：抗病毒治疗可有效预防艾滋病毒感染者的艾滋病，然而，越来越多的艾滋病毒感染者患有甚至死于艾滋病以外的疾病，包括心血管疾病。这些临床观察结果背后的生物学原理并不明确。众所周知，尽管抗逆转录病毒治疗（ART）依赖和独立机制似乎都参与其中，但我们计划研究艾滋病毒引起内皮激活和功能障碍的关键机制，这被认为是先于动脉粥样硬化发生的。众所周知，Nef 在 HIV 发病机制中发挥着关键作用，并介导其从 T 细胞到旁观细胞的转移，因此，我们假设 HIV-Nef 可以有效地从 T 细胞转移到包括血管内皮在内的其他血细胞。事实上，我们可以证明 Nef 的转移会导致内皮细胞活化和细胞死亡，根据我们发表的数据，这可以被 NADPH 氧化酶抑制剂和抗氧化剂有效消除。 HIV依赖性内皮激活可以通过Nef从血细胞转移到冠状动脉内皮细胞来解释，我们进一步认为Nef转移到血管细胞可能导致心血管功能障碍和心血管系统病理。我们计划在临床前体外和体内模型中研究 Nef 转移的机制及其活性我们预计，确定这些靶点将有助于使用适当的抑制剂进行临床干预研究，因此，确定血管内皮细胞中 Nef 诱导的血管病理学的细胞机制有助于将 HIV-Nef 确定为预防和治疗 HIV 的新靶点。 - 相关疾病。