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（由申请人提供）：本研究利用疱疹病毒转运蛋白 US9 的自然特征作为研究并可能调节与 HIV 相关神经认知障碍（HAND）相关的脂筏依赖性细胞过程的新方法，作为脂筏动态平台。由于这些条件可能涉及关键分子事件，我们的研究将利用 US9 特性来追踪 HIV 诱导的脂筏变化，并改变淀粉样前体蛋白 (APP) 的加工 - 对于这两种机制拟议的实验将检验以下假设：HIV-1 gp120/tat 有利于淀粉样蛋白生成酶转运至膜微结构域，从而导致神经毒性，并且这些病毒蛋白不会影响 US9 的神经元内分布。以及能够直接研究 HIV-1 蛋白诱导的脂筏变化和淀粉样蛋白生成之间的联系的强大策略，并可能发现一种减少神经元功能障碍的新治疗方法。 US9 作为神经元蛋白运输的分子示踪剂，用于研究 HIV-1 gp120 和 tat 在参与神经毒性的脂筏相关蛋白的神经元内分布中引起的改变 - 包括但不限于 APP 加工酶（目标 1）此外，通过 US9 介导的改变 APP 加工的工程酶的靶向，我们将增加细胞酶的表达，将 APP 加工转向非淀粉样蛋白生成途径，并测试神经毒性。 HIV 蛋白在这些条件下的影响（目标 2）为了确定病毒蛋白的体外和体内影响，这些目标包括在原代神经培养物和小动物模型中进行实验，如果成功，这项研究将有助于描述。脂筏变化在艾滋病毒引起的神经元损伤中的作用，确定淀粉样蛋白生成和神经元存活/损伤之间的联系，并导致旨在减少疾病晚期有害蛋白质局部积累的潜在应用。这个的范围研究成果具有高度创新性和重大意义，有望对HAND领域产生重大影响。