Neuroprotection by IFN-beta in AIDS

IFN-β 在艾滋病中的神经保护作用

基本信息

批准号：
8080301
负责人：
MARCUS KAUL
金额：
$ 44.91万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8080301
关键词：
Acquired Immunodeficiency Syndrome Affect Anti-Inflammatory Agents Anti-inflammatory Apoptotic Astrocytes Autoimmune Diseases Behavior Behavioral Blood - brain barrier anatomy Brain Bypass CCR5 gene Cells Cognition Dementia Dendrites Disease Disease Progression Drug Delivery Systems Exposure to FDA approved Future Gliosis Glycogen Synthase Kinases HIV HIV Envelope Protein gp120 HIV-1 Immune Immune response Immunosuppression Impaired cognition Impairment In Vitro Infection Inflammation Inflammatory Interferon-beta Interferons Laboratories Ligands Link Lymphocyte Macrophage Inflammatory Protein-1 Memory Microglia Mitogen-Activated Protein Kinases Molecular Multiple Sclerosis Nerve Degeneration Nerve Growth Factors Neuraxis Neurocognitive Neuronal Injury Neurons Performance Pharmaceutical Preparations Phosphotransferases Process Production Public Health RANTES Research Route SIV Signal Transduction Stress Synapses Testing Toxic effect Transgenic Mice Viral Virus Diseases Work base chemokine cytokine human MAPK14 protein immune activation improved in vitro Model in vivo macrophage mouse model neurogenesis neuropathology neuroprotection neurotoxic neurotoxicity pathogen prevent public health relevance tau Proteins tau phosphorylation therapeutic target

Acquired Immunodeficiency Syndrome Affect Anti-Inflammatory Agents Anti-inflammatory Apoptotic Astrocytes Autoimmune Diseases Behavior Behavioral Blood - brain barrier anatomy Brain Bypass CCR5 gene Cells Cognition Dementia Dendrites Disease Disease Progression Drug Delivery Systems Exposure to FDA approved Future Gliosis Glycogen Synthase Kinases HIV HIV Envelope Protein gp120 HIV-1 Immune Immune response Immunosuppression Impaired cognition Impairment In Vitro Infection Inflammation Inflammatory Interferon-beta Interferons Laboratories Ligands Link Lymphocyte Macrophage Inflammatory Protein-1 Memory Microglia Mitogen-Activated Protein Kinases Molecular Multiple Sclerosis Nerve Degeneration Nerve Growth Factors Neuraxis Neurocognitive Neuronal Injury Neurons Performance Pharmaceutical Preparations Phosphotransferases Process Production Public Health RANTES Research Route SIV Signal Transduction Stress Synapses Testing Toxic effect Transgenic Mice Viral Virus Diseases Work base chemokine cytokine human MAPK14 protein immune activation improved in vitro Model in vivo macrophage mouse model neurogenesis neuropathology neuroprotection neurotoxic neurotoxicity pathogen prevent public health relevance tau Proteins tau phosphorylation therapeutic target

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项目摘要

DESCRIPTION (provided by applicant): Infection with Human Immunodeficiency virus (HIV)-1 can induce dementia for which currently no treatment is available. Research in our and other laboratories strongly suggests that neurodegeneration occurs as a consequence of HIV-1 infection and neurotoxic immune stimulation of microglia and macrophages (M?) in the brain and impairment of neurogenesis. Beyond activation of M? and microglia, infection with HIV-1 triggers an innate immune response that includes production of interferons (IFNs). While IFNs are important for an anti-viral immune response, the lasting expression of IFN? in the HIV-1 exposed central nervous system (CNS) has been connected to cognitive impairment and inflammatory neuropathology. In contrast, IFN? has been implicated in the control of HIV infection in the brain. IFN? induces in M? and microglia natural ligands of the HIV coreceptor CCR5, such as MIP-1??? and RANTES, which inhibit HIV-1 infection. IFN? also induces the expression of nerve growth factor (NGF) and has pronounced anti-inflammatory effects. We found in preliminary studies that IFN? protected cerebrocortical neurons against neurotoxicity of HIV/gp120 while increasing baseline levels of RANTES. We also observed that RANTES and MIP-1? via CCR5 reduce the activity of the pro-inflammatory and stress-related p38 mitogen activated protein kinase (MAPK) and protect cerebrocortical neurons against neurotoxicity of HIV/gp120 in an Akt-dependent manner. Therefore, we propose to characterize the apparent neuroprotective effect of IFN? against toxicity of HIV/gp120 using in vivo and in vitro models. We hypothesize that IFN? can inhibit HIV/gp120 from inducing neuronal damage and impairing neurogenesis and compromising memory and cognition by a unique combination of mechanisms, comprising the induction of neuroprotective ?-chemokines and neurotrophic NGF. The long-term objectives are to find new potential treatments for HIV-associated dementia. The specific aims are: (1) To study in vivo whether IFN? prevents neuronal damage in a HIV/gp120 transgenic mouse model. (2) To assess in vitro whether the interaction of IFN? with microglia or M? suffices to prevent induction of HIV/gp120 neurotoxicity. (3) To investigate whether the interaction of IFN? with neurons and astrocytes suffices to protect the cells against HIV/gp120-induced neurotoxicity of microglia. For Specific Aim 1, IFN? will be administered via an intranasal route, which largely allows bypassing the blood brain barrier while delivering the drug to the brain. Memory and cognition-based behavioral performance, neuronal injury, neurogenesis and gliosis will be compared in IFN?- versus vehicle-treated HIV/gp120-transgenic mice. All three Specific Aims will test the premise that IFN? induces neuroprotective ?-chemokines and NGF, increases activity of Akt, reduces activity of p38 MAPK and glycogen synthase kinase (GSK) 32 and hyperphosphorylation of tau, and thus protects neurons and their dendrites and synapses from HIV/gp120-induced damage. We will also assess whether IFN? can preserve neurogenesis, memory and cognition and reduce gliosis in the presence of HIV/gp120. PUBLIC HEALTH RELEVANCE: HIV infection, AIDS and HIV-associated dementia remain a substantial public health concern and the proposed research aims at finding improved treatments by better understanding the disease process and the neuroprotective potential of the anti-viral cytokine interferon-?. Thus the proposed work will help to identify future therapeutic targets and thus new potential treatments for HIV-associated dementia via the analysis of intercellular and intracellular signaling mechanisms affected by the viral pathogen and host cytokines.

描述（由申请人提供）：患有人类免疫缺陷病毒（HIV）-1的感染可以诱导目前尚无治疗的痴呆。在我们和其他实验室中的研究强烈表明，由于HIV-1感染以及神经毒性的免疫刺激，大脑中的小胶质细胞和巨噬细胞（M？）是神经退行性的，因此发生了神经退行性。超越M的激活？和小胶质细胞，HIV-1感染触发了一种先天免疫反应，其中包括产生干扰素（IFNS）。 IFN对于抗病毒免疫反应很重要，而IFN的持久表达？在HIV-1中，暴露的中枢神经系统（CNS）与认知障碍和炎症性神经病理学有关。相反，IFN？与控制大脑中的艾滋病毒感染有关。 ifn？诱导M？ HIV共受体CCR5的小胶质细胞天然配体，例如MIP-1 ???和rantes，抑制HIV-1感染。 ifn？还诱导神经生长因子（NGF）的表达，并具有明显的抗炎作用。我们在初步研究中发现IFN？保护脑皮层神经元免受HIV/GP120的神经毒性的影响，同时增加了基线水平。我们还观察到Rantes和MIP-1？通过CCR5降低了促炎和应力相关的p38促丝分裂激活蛋白激酶（MAPK）的活性，并以Akt依赖性方式保护HIV/GP120的神经毒性侵袭性神经毒性。因此，我们建议表征IFN的明显神经保护作用？使用体内和体外模型抵抗HIV/GP120的毒性。我们假设IFN？可以通过独特的机制组合抑制HIV/GP120，从而抑制神经元损害，神经发生以及损害记忆和认知，包括神经保护性的诱导神经保护症？ - 肉体因子和神经营养性NGF。长期目标是为艾滋病毒相关痴呆症找到新的潜在治疗方法。具体目的是：（1）在体内研究是否IFN？防止HIV/GP120转基因小鼠模型中的神经元损伤。（2）在体外评估IFN的相互作用？与小胶质细胞或M？足以防止诱导HIV/GP120神经毒性。（3）调查IFN的相互作用？神经元和星形胶质细胞足以保护细胞免受小胶质细胞的HIV/GP120诱导的神经毒性。对于特定的目标1，IFN？将通过鼻内途径进行管理，该途径在很大程度上允许在将药物输送到大脑时绕过血脑屏障。在IFN？ - 与媒介物处理的HIV/GP120-TRANSGENIC小鼠相比，将比较基于记忆和基于认知的行为性能，神经元损伤，神经发生和神经病。所有三个特定目标都将测试IFN的前提？诱导神经保护作用？ - 化学因子和NGF，增加了AKT的活性，减少了p38 MAPK和糖原合酶激酶（GSK）32的活性和Tau的热磷酸化，从而保护神经元及其树突和突触HIV/GP120诱导的损害。我们还将评估IFN是否？可以保留神经发生，记忆和认知，并在HIV/GP120的存在下减少神经胶质病。公共卫生相关性：艾滋病毒感染，艾滋病和与艾滋病毒相关的痴呆仍然是一个很大的公共卫生问题，拟议的研究旨在通过更好地了解疾病过程和抗病毒细胞因子干扰素的神经保护潜力来找到改进的治疗方法。因此，提出的工作将有助于确定未来的治疗靶标，从而通过分析受病毒病原体和宿主细胞因子影响的细胞间和细胞内信号传导机制分析，从而确定与HIV相关痴呆的新潜在治疗方法。