Role of proBDNF and p75NTR in HIV-mediated axonal/dendritic degeneration

proBDNF 和 p75NTR 在 HIV 介导的轴突/树突变性中的作用

基本信息

批准号：
8551768
负责人：
Italo Mocchetti
金额：
$ 47.93万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8551768
关键词：
AIDS Dementia Complex Affect Affinity Animal Model Anti-Retroviral Agents Autopsy Basal Ganglia Binding Biological Brain Brain-Derived Neurotrophic Factor Cells Central Nervous System Infections Cleaved cell Data Dementia Disease Distress Enzymes Event Exhibits Family HIV HIV Envelope Protein gp120 HIV-1 Human Impaired cognition In Vitro Individual Infection Inflammation Inflammatory Response Injury Invaded Investigation Lead Life Longevity Matrix Metalloproteinases Mediating Microglia Minor Molecular Mutant Strains Mice NGFR Protein Nerve Degeneration Nerve Growth Factor Receptors Nervous system structure Neurocognitive Neurocognitive Deficit Neurologic Neurologic Deficit Neurologic Dysfunctions Neuronal Injury Neurons Pathologic Processes Pathology Peptide Hydrolases Plasmin Poison Presynaptic Terminals Prevalence Process Property Prosencephalon Rattus Resistance Rodent Role Signal Transduction Staging Synapses Syndrome Testing Transgenic Organisms Tumor Necrosis Factor-alpha Variant Viral Envelope Proteins Viral Proteins Virus axon growth axonal degeneration brain-derived neurotrophic factor precursor caspase-6 cellular imaging cytokine design effective therapy env Gene Products enzyme activity inhibitor/antagonist injured macrophage member motor impairment neuron apoptosis neuron loss neuropathology neuroprotection neurotoxic neurotoxicity neurotrophic factor novel prevent research study

项目摘要

DESCRIPTION (provided by applicant): Human Immunodeficiency Virus-1 (HIV) infection of the central nervous system may cause a neurological syndrome termed HIV-associated neurocognitive disorders (HAND). HAND includes minor neurocognitive disorders and a more severe form of motor and cognitive impairments termed HIV associated dementia (HAD). Although treatment with highly active antiretroviral agents decreases the load of HIV in the brain, the prevalence of HAND is actually increased due to longer life. Therefore, adjunctive and combined therapies must be developed to prevent and perhaps reverse the neurologic deficits observed in these individuals. These subjects exhibit synaptic simplification and neuronal apoptosis. However, the molecular mechanisms leading to synaptic pathology are unknown. Key to developing effective therapies is a better understanding of the molecular and cellular mechanisms by which the virus causes these neuropathological features. HIV and its viral envelope protein gp120 promote axonal retraction and dendritic simplification. These effects are reproduced by the proneurotrophin brain-derived neurotrophic factor (proBDNF) and are mediated by the p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor family. Thus, we have generated the hypothesis that proBDNF facilitates HIV neurotoxicity by promoting the activation of p75NTR. We have obtained preliminary data in support to this hypothesis. Indeed, we have shown that brains of HAD subjects exhibit a higher amount of proBDNF than non-HAD subjects. Moreover, in vitro data have determined that HIV and gp120-mediated synaptodendritic simplification is blocked by p75NTR antagonists. Thus, this proposal will test the novel hypothesis that HIV injures neurons by a gp120-mediated mechanism that involves the release of proBDNF, which in turn promotes axonal/dendritic degeneration via a p75NTR-mediated mechanism. Experiments will be carried out to establish the role of p75NTR in HIV/gp120 mediated neurotoxicity, and the cellular mechanisms whereby HIV/gp120 promotes proBDNF accumulation. These include testing the activity of enzymes involved in processing proBDNF to mature BDNF. These experiments will be accompanied by studies examining proteolytic enzymes involved in proBDNF processing in postmortem human brain as well as in animal models of HAD. Studies are also planned to establish the relationship (if any) between proBDNF and microglia activation and inflammation. We expect to provide new significant data on the role of p75NTR in HIV neurotoxicity. These data will help in the design of p75NTR antagonists as an adjunct therapy against synaptic simplification caused by HIV.

描述（由申请人提供）：中枢神经系统的人类免疫缺陷病毒 1 (HIV) 感染可能会导致称为 HIV 相关神经认知障碍 (HAND) 的神经系统综合征。 HAND 包括轻微的神经认知障碍和一种更严重的运动和认知障碍，称为 HIV 相关痴呆 (HAD)。尽管使用高活性抗逆转录病毒药物治疗可以减少大脑中的艾滋病毒负荷，但由于寿命延长，HAND 的患病率实际上有所增加。因此，必须开发辅助和联合疗法来预防并可能逆转这些个体中观察到的神经功能缺陷。这些受试者表现出突触简化和神经元凋亡。然而，导致突触病理学的分子机制尚不清楚。开发有效疗法的关键是更好地了解病毒引起这些神经病理学特征的分子和细胞机制。 HIV 及其病毒包膜蛋白 gp120 促进轴突回缩和树突简化。这些作用由前神经营养蛋白脑源性神经营养因子 (proBDNF) 再现，并由肿瘤坏死因子家族成员 p75 神经营养蛋白受体 (p75NTR) 介导。因此，我们提出了这样的假设：proBDNF 通过促进 p75NTR 的激活来促进 HIV 神经毒性。我们已经获得了支持这一假设的初步数据。事实上，我们已经证明，HAD 受试者的大脑比非 HAD 受试者表现出更高含量的 proBDNF。此外，体外数据已确定 HIV 和 gp120 介导的突触树突简化被 p75NTR 拮抗剂阻断。因此，该提案将检验新的假设，即 HIV 通过 gp120 介导的机制损伤神经元，该机制涉及 proBDNF 的释放，而 proBDNF 反过来又通过 p75NTR 介导的机制促进轴突/树突变性。将进行实验以确定 p75NTR 在 HIV/gp120 介导的神经毒性中的作用，以及 HIV/gp120 促进 proBDNF 积累的细胞机制。其中包括测试将 proBDNF 加工成成熟 BDNF 所涉及的酶的活性。这些实验将伴随着对死后人脑以及 HAD 动物模型中 proBDNF 加工所涉及的蛋白水解酶的研究。还计划进行研究以确定 proBDNF 与小胶质细胞激活和炎症之间的关系（如果有的话）。我们期望提供有关 p75NTR 在 HIV 神经毒性中的作用的新的重要数据。这些数据将有助于设计 p75NTR 拮抗剂作为针对 HIV 引起的突触简化的辅助疗法。