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

• 批准号: 9318486
• 负责人: Olimpia Meucci
• 金额: $ 20.02万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 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/9318486
• 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; Comorbidity; 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; Intervention; 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; Subgroup; Surface; Techniques; Testing; Tissues; Tracer; Transport Vesicles; Vesicle; Vesicle Transport Pathway; Viral; Viral Proteins; Virion; Work; abeta accumulation; abeta deposition; age related; alpha secretase; amyloid precursor protein processing; amyloidogenesis; beta secretase; cellular imaging; experimental study; 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; response; tool; trans-Golgi Network

 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。由于脂筏代表了可能与这些情况有关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 - 用于机械和干预目的。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。这项工作将产生一种新的、强大的策略，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，并可能发现一种减少神经元功能障碍的新治疗方法。简而言之，我们将使用 US9 作为神经元蛋白质运输的分子示踪剂，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 HIV 蛋白在这些条件下的神经毒性作用（目标 2）。为了确定病毒蛋白的体外和体内效应，这些目标包括在原代神经元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，并带来旨在减少疾病晚期有害蛋白质局部积累的潜在应用。因此，本研究的技术方法和研究范围都具有很强的创新性和意义，有望对HAND领域产生实质性影响。