Cellular and molecular mechanisms of gp120 neurotoxicity

gp120神经毒性的细胞和分子机制

基本信息

批准号：
8337704
负责人：
Italo Mocchetti
金额：
$ 19.39万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8337704
关键词：
AIDS Dementia Complex Affect Apoptosis Apoptotic Axon Axonal Transport Back Behavioral Binding Biochemical Brain CXCR4 Receptors CXCR4 gene Cells Cytoplasmic Organelle Cytoskeleton Data Dementia Development Disease Dynein ATPase Endocytosis Endosomes Event Exhibits Functional disorder Glycoproteins Goals HIV HIV Envelope Protein gp120 HIV-1 Impaired cognition In Vitro Individual Infection Inflammatory Inflammatory Response Injury Invaded Investigation Kinesin Knowledge Lead Length Lysosomes Maintenance Mediating Membrane Microtubule-Associated Proteins Microtubules Mitochondria Molecular Motor Mus Nature Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurologic Neurons Neurotoxins Organelles Pathology Pathway interactions Pattern Phosphorylation Phosphotransferases Physiological Play Process Proteins Rattus Rodent Role Series Signal Pathway Site Sorting - Cell Movement Spinal Ganglia Staging Survival Rate Symptoms Synapses Testing Time Toxic effect Tubulin Vascularization Viral Envelope Proteins Viral Proteins Virus axonal degeneration base caspase-3 chemokine receptor cytokine design effective therapy env Gene Products fast axonal transport immunoreactivity in vivo inhibitor/antagonist injured neuron apoptosis neuron loss neuronal cell body neuronal survival neurotoxic neurotoxicity overexpression postsynaptic presynaptic prevent protein expression receptor research study tau Proteins

项目摘要

DESCRIPTION (provided by applicant): Axonal injury is seen in subjects with Human Immunodeficiency Virus type 1 (HIV) associated dementia (HAD). The lack of documented evidence of direct infection of neurons by HIV has prompted studies to reveal possible mechanisms for HIV-mediated axonal damage. However, the nature and the site of initial injury to the neuron are unknown; in particular it is unclear if the process starts in the axons itself or in the neuronal cell body. Several lines of independent investigations have shown that the viral envelope protein gp120 promotes neuronal degeneration. The neurotoxic effect of gp120 occurs through chemokine receptors. Preliminary evidence has shown that the chemokine receptor CXCR4 promotes endocytosis of T-tropic gp120 into neurons. Endocytosis of gp120 is followed by axonal transport through microtubules. The length of axons and survival rate of neurons that do not internalize gp120 is significantly greater when compared to those accumulating gp120. Moreover, agents that block axonal transport are neuroprotective against gp120 even in the presence of cytokines, suggesting that the toxic effect of gp120 may not necessarily require an inflammatory response. Most importantly, gp120 endocytosis and transport precede synaptic simplification and caspase-3 activation and therefore neuronal cell death, suggesting that accumulation and axonal transport of gp120 are crucial to its toxicity. These data lead to a new challenging hypothesis that gp120 binding to CXCR4 receptor initiates a series of events that triggers direct axonal toxicity. However, little is known about the cellular and molecular mechanisms of this effect. Internalized gp120 could cause axonal damage and neuronal apoptosis by affecting axonal proteins or impairing the axonal transport of important molecules that are necessary for neuronal survival and maintenance. The experiments planned in this project will examine whether gp120 affects selected regulatory kinases of axonal transport, or microtubule-associated protein such as Tau, or other cytoskeleton proteins that when impaired, promote the "dying-back" pattern of degeneration. These experiments will be accompanied by histological analysis of gp120 immunoreactivity within endosomes or other cellular organelles, as well as by biochemical analyses of pro-inflammatory cytokines. The ability of gp120 to induce a rapid axonal/dendritic degeneration raises the hypothesis that this protein is sufficient to initiate an irreversible neurodegenerative process even in the absence of other endogenous neurotoxins or other patho-physiological insults. If proven, our hypothesis that gp120 injures neurons by being internalized and transported to their cell bodies will lead to a major discovery in this field. Overall, we expect to provide new significant data that help in the design of adjunct therapies against synaptic simplifications caused by HIV.

描述（由申请人提供）：轴突损伤见于患有 1 型人类免疫缺陷病毒 (HIV) 相关痴呆 (HAD) 的受试者。由于缺乏 HIV 直接感染神经元的证据，促使研究揭示 HIV 介导的轴突损伤的可能机制。然而，神经元最初损伤的性质和部位尚不清楚；特别是尚不清楚该过程是从轴突本身还是从神经元细胞体开始。多项独立研究表明，病毒包膜蛋白 gp120 会促进神经元变性。 gp120 的神经毒性作用通过趋化因子受体发生。初步证据表明趋化因子受体CXCR4促进T-tropic gp120内吞进入神经元。 gp120 的内吞作用之后是通过微管的轴突运输。与积累 gp120 的神经元相比，未内化 gp120 的神经元的轴突长度和存活率显着更高。此外，即使在细胞因子存在的情况下，阻断轴突运输的药物也能对 gp120 产生神经保护作用，这表明 gp120 的毒性作用可能不一定需要炎症反应。最重要的是，gp120 的内吞作用和运输先于突触简化和 caspase-3 激活，从而导致神经元细胞死亡，这表明 gp120 的积累和轴突运输对其毒性至关重要。这些数据引发了一个新的具有挑战性的假设，即 gp120 与 CXCR4 受体结合引发了一系列引发直接轴突毒性的事件。然而，人们对这种效应的细胞和分子机制知之甚少。内化的 gp120 可能通过影响轴突蛋白或损害神经元生存和维持所必需的重要分子的轴突运输而导致轴突损伤和神经元凋亡。该项目计划的实验将检查 gp120 是否影响轴突运输的选定调节激酶、微管相关蛋白（如 Tau）或其他细胞骨架蛋白，这些蛋白在受损时会促进“死亡”退化模式。这些实验将伴随内体或其他细胞器内 gp120 免疫反应性的组织学分析，以及促炎细胞因子的生化分析。 gp120 诱导快速轴突/树突变性的能力提出了这样的假设：即使在没有其他内源性神经毒素或其他病理生理损伤的情况下，该蛋白也足以启动不可逆的神经退行性过程。如果得到证实，我们关于 gp120 通过内化并转运到细胞体来损伤神经元的假设将导致该领域的重大发现。总的来说，我们期望提供新的重要数据，帮助设计针对艾滋病毒引起的突触简化的辅助疗法。