Effects of HIV-1 neurotoxins on lipid rafts-associated proteins

HIV-1神经毒素对脂筏相关蛋白的影响

基本信息

批准号：
9072126
负责人：
Olimpia Meucci
金额：
$ 23.05万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9072126
关键词：
Abeta synthesis Affect Aging Aging-Related Process Amyloid beta-Protein Animal Model Anti-Retroviral Agents Axonal Transport Biochemistry Brain Carrier Proteins Cell physiology Cells Chimera organism Chimeric Proteins Chronic Complex Destinations Disease Drug abuse Drug user Engineering Enzymes Equilibrium Event HIV HIV Envelope Protein gp120 HIV-1 HIV-associated neurocognitive disorder Health Herpesviridae Herpesvirus 1 Impaired cognition In Vitro Infection Injury Lead Life Life Expectancy Link Mediating Membrane Microdomains Molecular Molecular Virology Monitor N-Methyl-D-Aspartate Receptors N-Methylaspartate NR1 NMDA receptor Neurocognitive Deficit Neuronal Dysfunction Neuronal Injury Neurons Neurotoxins Pathway interactions Patients Peripheral Physiological Population Prevalence Process Property Proteins Reporter Research Role Signal Pathway Sorting - Cell Movement Staging Subgroup Surface Techniques Testing Tissues Tracer Transport Vesicles Vesicle Viral Viral Proteins Virion Work abeta accumulation abeta deposition age related alpha secretase amyloid precursor protein processing amyloidogenesis beta secretase cellular imaging high risk improved in vivo innovation insight neuronal survival neuronal transport neurotoxic neurotoxicity novel strategies novel therapeutic intervention protein transport public health relevance red fluorescent protein release of sequestered calcium ion into cytoplasm research study response tool trans-Golgi Network

项目摘要

DESCRIPTION (provided by applicant): This research exploits natural features of the herpesvirus transport protein US9 as a novel approach to study, and possibly modulate, lipid rafts dependent cellular processes relevant to HIV Associated Neurocognitive Disorders (HAND). As lipid rafts represent dynamic platforms for key molecular events likely involved in these conditions, our studies will capitalize on US9 properties to trace HIV-induced changes in lipid rafts, and alter Amyloid Precursor Protein (APP) processing - for both mechanistic and interventional purposes. The proposed experiments will test the hypothesis that HIV-1 gp120/tat favor transport of amyloidogenic enzymes to membrane microdomains, leading to neurotoxicity, and that these viral proteins do not affect intraneuronal distribution of US9. This work will generate a new and powerful strategy capable of studying directly the link between HIV-1 proteins induced changes of lipid rafts and amyloidogenesis, as well as possibly discovering a novel therapeutic approach to decreasing neuronal dysfunction. Briefly, we will use US9 as a molecular tracer of neuronal protein transport to study alterations induced by HIV-1 gp120 and tat in the intraneuronal distribution of lipid rafts-associated proteins that are involved in neurotoxiciy - including, but not limited to, APP processing enzymes (Aim 1). Moreover, through US9-mediated targeting of engineered enzymes altering APP processing, we will increase expression of cellular enzymes that shift APP processing toward the non-amyloidogenic pathway and test the neurotoxic effects of the HIV proteins under these conditions (Aim 2). In order to determine both in vitro and in vivo effects of the viral proteins, these aims include experiments in primary neuronal cultures and small animal models. If successful, this research will help delineate the role of lipid rafts changes in HIV-induced neuronal damage, determine the link between amyloidogenesis and neuronal survival/injury, and lead to potential applications intended to reduce local accumulation of noxious proteins at advanced stages of disease. Thus, both the technical approach and scope of this research are highly innovative and significant, and expected to exert a substantial impact on the field of HAND.

描述（由适用提供）：本研究探讨了疱疹病毒转运蛋白US9的自然特征，作为一种新型研究方法，并可能调节脂质筏依赖于与HIV相关的神经认知障碍有关的细胞过程（手）。由于脂质筏代表了可能涉及这些条件的关键分子事件的动态平台，因此我们的研究将利用US9特性，以追踪HIV诱导的脂质筏的变化，并改变淀粉样蛋白前体蛋白（APP）处理 - 用于机械和介入目的。提出的实验将检验以下假设：HIV-1 GP120/TAT有利于将淀粉样蛋白生成酶转运到膜微区域，从而导致神经毒性，并且这些病毒蛋白不影响US9的神经内神经元分布。这项工作将产生一种新的强大策略，能够直接研究HIV-1蛋白之间的联系，引起脂质筏的变化和淀粉样蛋白发生的变化，以及可能发现一种新型的治疗方法来降低神经元功能障碍。简而言之，我们将使用US9作为神经元蛋白转运的分子示踪剂来研究由HIV-1 GP120和TAT诱导的变化，并在脂质筏相关蛋白的植物内神经元分布中与神经毒性相关的蛋白质的神经元分布（包括，包括，不限于App Processing enzymes（AIM 1）。此外，通过US9介导的工程酶改变APP加工的靶向，我们将增加细胞酶的表达，这些酶的表达将APP处理转移到非淀粉样蛋白途径并测试HIV蛋白在这些条件下的神经毒性作用（AIM 2）。为了确定病毒蛋白的体外和体内效应，这些目的包括在原发性神经元培养物和小动物模型中的实验。如果成功，这项研究将有助于描述脂质筏在HIV引起的神经元损伤中的变化，确定淀粉样生成与神经元存活/损伤之间的联系，并导致潜在的应用，旨在减少疾病高级阶段有害蛋白质的局部积累。这是这项研究的技术方法和范围具有很高的创新性和重要意义，并有望对手领域产生重大影响。