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：
8449221
负责人：
MARCUS KAUL
金额：
$ 44.02万
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/8449221
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

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.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）-1 感染可诱发痴呆，目前尚无治疗方法。我们和其他实验室的研究强烈表明，神经变性是由于 HIV-1 感染、大脑中小胶质细胞和巨噬细胞 (M?) 的神经毒性免疫刺激以及神经发生受损而发生的。除了激活M？和小胶质细胞，HIV-1 感染会引发先天免疫反应，包括产生干扰素 (IFN)。虽然干扰素对于抗病毒免疫反应很重要，但干扰素的持久表达？ HIV-1 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。相比之下，干扰素?与大脑中艾滋病毒感染的控制有关。干扰素？诱导 M?以及 HIV 辅助受体 CCR5 的小胶质细胞天然配体，例如 MIP-1？？？和 RANTES，可抑制 HIV-1 感染。干扰素？还诱导神经生长因子（NGF）的表达并具有显着的抗炎作用。我们在初步研究中发现，干扰素？保护大脑皮层神经元免受 HIV/gp120 的神经毒性，同时增加 RANTES 的基线水平。我们还观察到RANTES和MIP-1？通过 CCR5 降低促炎和应激相关的 p38 丝裂原激活蛋白激酶 (MAPK) 的活性，并以 Akt 依赖性方式保护大脑皮质神经元免受 HIV/gp120 的神经毒性。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对抗 HIV/gp120 的毒性。我们假设干扰素？可以通过独特的机制组合（包括诱导神经保护性 β-趋化因子和神经营养性 NGF）抑制 HIV/gp120 诱导神经元损伤、损害神经发生以及损害记忆和认知。长期目标是寻找治疗艾滋病毒相关痴呆症的新的潜在疗法。具体目的是：（1）研究体内是否有IFN？预防 HIV/gp120 转基因小鼠模型中的神经元损伤。 (2)在体外评价IFN是否有相互作用？与小胶质细胞或M？足以防止诱导HIV/gp120神经毒性。 (3)探讨IFN是否有相互作用？与神经元和星形胶质细胞的结合足以保护细胞免受 HIV/gp120 诱导的小胶质细胞的神经毒性。对于具体目标 1，干扰素？将通过鼻内途径给药，这在很大程度上允许绕过血脑屏障，同时将药物输送到大脑。将比较IFNα-与媒介物处理的HIV/gp120转基因小鼠中基于记忆和认知的行为表现、神经元损伤、神经发生和神经胶质增生。所有三个具体目标都将测试干扰素？诱导神经保护性 β-趋化因子和 NGF，增加 Akt 活性，降低 p38 MAPK 和糖原合酶激酶 (GSK) 32 的活性以及 tau 的过度磷酸化，从而保护神经元及其树突和突触免受 HIV/gp120 诱导的损伤。我们还会评估是否有IFN？可以保护神经发生、记忆和认知，并在 HIV/gp120 存在的情况下减少神经胶质增生。