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

• 批准号: 8466684
• 负责人: Italo Mocchetti
• 金额: $ 48.52万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 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/8466684
• 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

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. PUBLIC HEALTH RELEVANCE: Human immunodeficiency virus type 1 (HIV) invades the brain and causes injury to neurons. Currently, there is no effective therapy to reverse HIV-mediated neuronal degeneration. Key to develop new therapies is the understanding of the mechanisms of HIV neurotoxicity. In this proposal, we will test the hypothesis that the virus promotes degeneration of neurons through its envelope protein gp120. This viral protein triggers the release of a toxic compound termed proBDNF. ProBDNF is neurotoxic because it activates the low affinity neurotrophin receptor (p75NTR). Therefore, we propose to explore the hypothesis that inhibitors of p75NTR will prevent the neurotoxic effect of HIV/gp120.

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相关的神经认知疾病（手）的神经系统综合征（手）。手包括次要的神经认知障碍，以及一种更严重的运动和认知障碍形式，称为HIV相关痴呆症（HAT）。尽管用高度活跃的抗逆转录病毒药物治疗降低了大脑中HIV的负荷，但由于寿命较长，手的患病率实际上增加了。因此，必须开发辅助疗法，以防止和扭转这些个体中观察到的神经系统缺陷。这些受试者表现出突触简化和神经元凋亡。但是，导致突触病理的分子机制尚不清楚。开发有效疗法的关键是对病毒引起这些神经病理学特征的分子和细胞机制的更好理解。 HIV及其病毒包膜蛋白GP120促进轴突缩回和树突简化。这些作用是由脑营养素衍生的神经营养因子（ProbDNF）再现的，并由肿瘤坏死因子家族的成员P75神经营养蛋白受体（P75NTR）介导。因此，我们已经产生了这样的假设，即通过促进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。确实，我们已经表明，与非HAD受试者相比，HAD受试者的大脑表现出更高的概率。此外，体外数据已经确定HIV和GP120介导的突触源性简化被P75NTR拮抗剂阻断。因此，该提案将检验一个新的假设，即HIV通过GP120介导的机制损害神经元，该机制涉及ProbDNF的释放，该机制又通过P75NTR介导的机制促进了轴突/树突状变性。将进行实验，以确定p75NTR在HIV/GP120介导的神经毒性中的作用，而HIV/GP120的细胞机制促进了ProbDNF的积累。其中包括测试与成熟BDNF一起处理ProbDNF的酶的活性。这些实验将伴随着研究参与尸体后人脑以及HAT动物模型中参与ProbDNF加工的蛋白水解酶的研究。还计划在ProbDNF和小胶质细胞激活和炎症之间建立关系（如果有的话）。我们希望提供有关p75NTR在HIV神经毒性中的作用的新重要数据。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。 公共卫生相关性：人类免疫缺陷病毒1型（HIV）侵入大脑并对神经元造成伤害。当前，尚无有效的疗法来逆转HIV介导的神经元变性。开发新疗法的关键是对HIV神经毒性机制的理解。在此提案中，我们将检验以下假设：病毒通过其包膜蛋白GP120促进神经元的变性。该病毒蛋白会触发称为probdnf的有毒化合物的释放。 ProbDNF具有神经毒性，因为它激活了低亲和力神经营养受体（P75NTR）。因此，我们建议探讨以下假设：p75NTR的抑制剂将防止HIV/GP120的神经毒性作用。