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：
9149313
负责人：
MARCUS KAUL
金额：
$ 64.37万
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 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9149313
关键词：
Acquired Immunodeficiency Syndrome Adult Affect Age-Months Animals Anti-Inflammatory Agents Anti-inflammatory Antiviral Agents Apoptotic Astrocytes Autoimmune Diseases Behavioral Biological Biological Models Blood - brain barrier anatomy Brain Brain Injuries Bypass CCL3 gene CCL4 gene Child Cognition Dementia Dendrites Development Disease Down-Regulation Drug Delivery Systems FDA approved Funding Future Gene Expression Profiling Genes Genetic Gliosis HIV HIV Envelope Protein gp120 HIV-1 HIV-associated neurocognitive disorder IFNAR1 gene IRF1 gene IRF3 gene Immune Immune response Immunosuppression Impaired cognition Impairment In Vitro Infection Inflammation Inflammatory Interferon-alpha Interferon-beta Interferons Laboratories Link MAP Kinase Gene MAPK14 gene Manuscripts Memory Microglia Molecular Mus Nerve Degeneration Neuraxis Neuronal Injury Neurons Neurotoxins Performance Pharmaceutical Preparations Phosphotransferases Preparation Process Production Protocols documentation Public Health RNA Recombinants Research Reverse Transcriptase Polymerase Chain Reaction Role Route SIV Signal Pathway Signal Transduction Stress Synapses Testing Therapeutic Toxic effect Transgenic Mice Viral Virus Diseases base behavioral impairment beta-Chemokines cell type cytokine genome-wide improved in vitro Model in vivo macrophage mouse model multiple sclerosis treatment neurocognitive disorder neurogenesis neuron loss neuropathology neuroprotection neurotoxic neurotoxicity novel prevent public health relevance receptor research study response therapeutic target transcriptome sequencing

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. Several lines of evidence strongly suggest that neurodegeneration occurs as a consequence of HIV-1 infection and neurotoxic immune stimulation of microglia and macrophages (MΦ) in the brain and impairment of neurogenesis. HIV-1 also triggers an innate immune response that includes production of interferons (IFNs). IFNβ has been implicated in the control of HIV infection in the brain and has pronounced anti-inflammatory effects. In the previous funding period we found: First, a CNS gene expression analysis of HIV/gp120 transgenic (tg) mice revealed a limited IFN response. HIV/gp120tg brains transiently expressed IFNβ at 1.5 but not 3 or 6 months of age when neuropathology and behavioral impairment developed. Second, we found that a four-week intranasal (i.n.) IFNβ treatment starting at 3.5 months of age completely prevented neuronal damage in HIV/gp120tg mice. Third, IFNβ protected neurons in vitro against neurotoxicity of HIV/gp120 by early induction of CCL3, which occurred most efficiently in the presence of microglia. In this renewal application we propose to characterize i) the contribution of the endogenous IFN response and ii) the cell type-specific role of IFNα/β receptor 1 (IFNAR1) and IFN-stimulated genes (ISGs) in neuroprotection by IFNβ against toxicity of HIV-1 or gp120. We hypothesize that IFNβ can protect neurons from HIV-1/gp120 induced toxicity and preserve behavioral performance by a mechanisms, comprising induction of neuroprotective IFN-stimulated genes (ISG) such as IRF1 and CCL3 and inhibition of inflammation. The specific aims are: (1) To study in vivo how endogenous IFNβ affects neuronal damage in a HIV/gp120 transgenic mouse model and the animals' response to intranasal IFNβ treatment. (2) To examine in vivo whether the interferon α/β receptor 1 (IFNAR1) of microglia or astrocytes or neurons are necessary for neuroprotection by IFNβ against toxicity of HIV/gp120. (3) To assess whether a continuous supply of exogenous IFNβ can restrict HIV-1 infection and the associated neurotoxicity of MΦ via induction of a subset of anti-viral ISGs. For Specific Aims 1 and 2, IFNβ will be administered via an intranasal route, which allows bypassing the blood brain barrier while delivering the drug to the brain. Memory and cognition-based behavioral performance, neuronal injury and gliosis will be compared in IFNβ- versus vehicle-treated HIV/gp120-transgenic mice lacking endogenous IFNβ or its receptor IFNAR1. We will also assess which neural cell type(s) are required to interact with IFNβ in order to preserve memory and cognition and to reduce gliosis in the presence of HIV/gp120. Specific Aim 3 will define an RNA signature of neurotoxic HIV-1 infected MΦ using RNA-sequencing and will test the premise that exogenous IFNβ can overcome the down- regulation of antiviral factors and production of neurotoxins by HIV-1. All three Specific Aims will test the premise that IFNβ induces neuroprotective β-chemokines, increases activity of Akt and reduces activity of p38 MAPK, and thus protects neurons and their dendrites and synapses from HIV or gp120-induced toxicity of microglia and MΦ.

描述（由适用提供）：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症。有几条证据强烈表明，由于HIV-1感染以及对大脑中小胶质细胞和巨噬细胞（Mφ）的神经毒性免疫刺激而发生神经退行性的结果。 HIV-1还触发了一种先天的免疫响应，其中包括产生干扰素（IFNS）。 IFNβ已在控制大脑中的HIV感染中隐含，并且具有明显的抗炎作用。在上一个资金期间，我们发现：首先，HIV/GP120转基因（TG）小鼠的CNS基因表达分析显示IFN反应有限。当神经病理学和行为障碍发展时，HIV/GP120TG大脑在1.5时瞬时表达IFNβ，但未3或6个月。其次，我们发现在3.5个月大时从3.5个月开始进行为期四周的IFNβ治疗完全阻止了HIV/GP120TG小鼠的神经元损伤。第三，IFNβ在体外保护神经元通过早期诱导CCL3来保护HIV/GP120的神经毒性，在小胶质细胞的情况下最有效地发生了。在此续签应用中，我们建议表征i）内源性IFN响应的贡献和ii）IFNα/β受体1（IFNAR1）和IFN刺激的基因（ISGS）在IFNβ中对HIV-1或GP120的毒性的神经保护中的细胞类型特异性作用。我们假设IFNβ可以保护神经元免受HIV-1/gp120的毒性诱导的毒性，并通过机制来保留行为性能，从而完成神经保护性IFN刺激基因（ISG）（例如IRF1和CCL3）的诱导以及炎症的抑制。具体目的是：（1）在体内研究内源性IFNβ如何影响HIV/GP120转基因小鼠模型中的神经元损伤，以及动物对鼻内IFNβ治疗的反应。（2）在体内检查小胶质细胞或星形胶质细胞或星形胶质细胞或神经元的干扰素α/β受体1（IFNAR1）是否是IFNβ对HIV/GP120毒性的神经保护是否必需的。（3）评估外源性IFNβ的连续供应是否可以通过诱导抗病毒ISG的子集来限制Mφ的HIV-1感染和Mφ的相关神经毒性。对于特定目标1和2，IFNβ 我们还将评估与IFNβ相互作用以保持记忆和认知需要哪种神经元细胞类型。并在HIV/GP120存在下减少神经病。特定的目标3将使用RNA序列定义神经毒性HIV-1感染Mφ的RNA特征，并将测试外源IFNβ可以克服抗病毒因子的下调和HIV-1神经毒素的下调的前提。所有三个特定目标都将测试IFNβ诱导神经保护性β化学因子，增加Akt的活性并减少p38 MAPK的活性的前提，从而保护HIV或GP120诱导的Microglia和M或Microglia和Mφ的毒性。