Role of proBNDF and p75NTR in HIV-mediated Axonal/Dendritic Degeneration

proBNDF 和 p75NTR 在 HIV 介导的轴突/树突变性中的作用

• 批准号: 10621350
• 负责人: Italo Mocchetti
• 金额: $ 54.6万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621350
• 关键词: Address; Adult; Affect; Affinity; Alleles; Animals; Apoptotic; Applications Grants; Area; Autopsy; Axon; Binding; Biological; Brain; Brain Diseases; Brain-Derived Neurotrophic Factor; Cells; Central Nervous System Infections; Cerebrospinal Fluid; Cognition; Data; Dendrites; Dendritic Spines; Diagnosis; Enzymes; Equilibrium; Excision; Exhibits; Exposure to; Functional disorder; Golgi Apparatus; Grant; HIV; HIV Envelope Protein gp120; HIV Seropositivity; HIV-1; HIV-associated neurocognitive disorder; Hippocampus; Human; Impaired cognition; Impairment; Investigation; Knockout Mice; Link; Measures; Mediating; Memory; Memory impairment; Microfluidics; Microtubules; Molecular; Mus; NGFR Protein; Nerve Degeneration; Nerve Growth Factor Receptors; Nervous System Trauma; Neurocognitive Deficit; Neurodegenerative Disorders; Neurologic Dysfunctions; Neuronal Injury; Neurons; Pathologic; Play; Poison; Rattus; Receptor Activation; Reproducibility; Research; Role; Sampling; Severities; Signal Transduction; Subgroup; Synapses; Testing; Toxic effect; Transgenic Mice; Transgenic Organisms; Vertebral column; Viral Proteins; antagonist; antiretroviral therapy; behavioral study; brain-derived neurotrophic factor precursor; env Gene Products; experimental study; induced pluripotent stem cell; nerve stem cell; neurocognitive disorder; neuronal survival; neuronal transport; neurotoxic; neurotoxicity; neurotrophic factor; novel; postsynaptic; presynaptic; prevent; receptor; transcriptional coactivator p75

Abstract Human immunodeficiency virus-1 (HIV) infection of the central nervous system damages synapses and promotes neuronal injury that culminates in HIV-associated neurocognitive disorders (HAND). How HIV damages synapses is still under investigation. Viral proteins, including the envelope protein gp120, have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanisms remain unclear. The balance between neuronal survival and damage is predominantly governed by neurotrophic factors, and in particular, brain-derived neurotrophic factor (BDNF) and its precursor proBDNF. proBDNF, when bound to the neurotrophin receptor p75 (p75NTR) activates a pro-apoptotic signal. We have shown that brains of HAND subjects, as well as neurons exposed to gp120, exhibit a significant increase of proBDNF, which correlates with a decreased expression of furin, a key enzyme in the processing of proBDNF. The removal of one allele of p75NTR, the receptor for proBDNF, rescues the loss of synapses seen in gp120 transgenic mice. Therefore, we hypothesize that HIV damages synapses through the ability of gp120 to increase proBDNF and therefore activating p75NTR. This is an important line of research because synaptic degeneration dysfunction has been linked to numerous neurodegenerative diseases but only preliminarily to HAND. The molecular and cellular mechanisms of how gp120 causes impairs/damages synapses remain under investigation. This application proposes a comprehensive set of experiments to test the main hypothesis. In particular (AIM 1), we will test the hypothesis that gp120 reduces furin levels by directly binding to this endoprotease. We will utilize (AIM 2) p75NTR-/- neurons and p75NTR antagonists to examine the mechanisms and signaling of gp120 neurotoxicity. We will perform behavioral studies for memory function (AIM 3) in gp120 transgenic (gp120tg) mice intercrossed with p75NTR null mice to investigate whether the removal of one allele for p75NTR rescues the memory impairment observed in gp120tg mice. Finally, (AIM 4) we will use human samples including the cerebrospinal fluid (CSF) to determine whether the levels of proBDNF are altered in different subgroups of HAND subjects. Levels of gp120 will also be measured in the CSF. These experiments might establish a correlation between levels of proBDNF, gp120 and neurocognitive impairment. We expect to provide new significant data on the role of p75NTR in HIV-mediated synaptic simplification.

抽象的 中枢神经系统损害突触和 促进神经元损伤，最终导致与HIV相关的神经认知疾病（手）。艾滋病毒 损害突触仍在调查中。病毒蛋白，包括包膜蛋白GP120，具有 尽管机制尚不清楚，但还是成为解释HIV介导的神经毒性的主要候选人。 神经元生存与损害之间的平衡主要由神经营养因素和在 特别是脑衍生的神经营养因子（BDNF）及其前体概率。当绑定到 神经营养蛋白受体P75（P75NTR）激活促凋亡信号。我们已经证明了手的大脑 受试者以及暴露于GP120的神经元表现出显着增加ProbDNF，这与 随着垂体的表达降低，ProbDNF处理中的键酶。去除一个等位基因 P75NTR的ProbDNF受体挽救了GP120转基因小鼠中突触的损失。 因此，我们假设HIV通过GP120的能力损害了突触 probdnf，因此激活p75ntr。这是一项重要的研究，因为突触 变性功能障碍已与许多神经退行性疾病有关，但仅是初步的 手。 GP120如何导致损害/损害突触的分子和细胞机制保留 正在调查。该应用程序提出了一组全面的实验，以检验主要假设。 特别是（AIM 1），我们将检验以下假设，即GP120通过直接结合而降低植物水平 内药物。我们将利用（AIM 2）P75NTR - / - 神经元和P75NTR拮抗剂来检查机制 GP120神经毒性的信号传导。我们将在GP120中进行记忆功能的行为研究（AIM 3） 转基因（GP120TG）小鼠与p75ntr null小鼠串在一起，以研究去除一个等位基因是否是否去除 对于P75NTR，可以挽救在GP120TG小鼠中观察到的记忆障碍。最后，（目标4）我们将使用人类 包括脑脊液（CSF）在内的样品，以确定ProbDNF的水平是否改变 手部对象的不同亚组。 GP120的水平也将在CSF中进行测量。这些实验 可能在ProbDNF，GP120和神经认知障碍的水平之间建立相关性。我们希望 提供有关p75NTR在HIV介导的突触简化中的作用的新重要数据。

项目成果

Synaptic dysfunction in human immunodeficiency virus type-1-positive subjects: inflammation or impaired neuronal plasticity?

• DOI: 10.1111/joim.12050
• 发表时间: 2013-05-01
• 期刊: JOURNAL OF INTERNAL MEDICINE
• 影响因子: 11.1
• 作者: Avdoshina, V.;Bachis, A.;Mocchetti, I.
• 通讯作者: Mocchetti, I.

Recent Advances in the Molecular and Cellular Mechanisms of gp120-Mediated Neurotoxicity.

• DOI: 10.3390/cells11101599
• 发表时间: 2022-05-10
• 期刊: Cells
• 影响因子: 6

CCL5 and cytokine expression in the rat brain: differential modulation by chronic morphine and morphine withdrawal.

• DOI: 10.1016/j.bbi.2013.08.006
• 发表时间: 2013-11
• 期刊: BRAIN BEHAVIOR AND IMMUNITY
• 影响因子: 15.1
• 作者: Campbell, Lee A.;Avdoshina, Valeriya;Rozzi, Summer;Mocchetti, Italo
• 通讯作者: Mocchetti, Italo

Up-regulation of the p75 neurotrophin receptor is an essential mechanism for HIV-gp120 mediated synaptic loss in the striatum.

• DOI: 10.1016/j.bbi.2020.07.023
• 发表时间: 2020-10
• 期刊: Brain, behavior, and immunity
• 作者: Speidell A;Asuni GP;Wakulski R;Mocchetti I
• 通讯作者: Mocchetti I

Human immunodeficiency virus type 1 alters brain-derived neurotrophic factor processing in neurons.

• DOI: 10.1523/jneurosci.0865-12.2012
• 发表时间: 2012-07-11
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Bachis A;Avdoshina V;Zecca L;Parsadanian M;Mocchetti I
• 通讯作者: Mocchetti I