Interferon-Alpha-Neurotoxicity

干扰素-α-神经毒性

• 批准号: 9275357
• 负责人: WILLIAM R TYOR
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275357
• 关键词: Adverse effects; Animals; Anti-Retroviral Agents; Antibodies; Antiviral Agents; Behavioral; Blood - brain barrier anatomy; Brain; Brain Diseases; Combined Modality Therapy; Data; Disease; Dose; Encephalitis; Exhibits; Exposure to; Functional disorder; Genes; Goals; Grant; HIV; HIV Infections; HIV encephalitis; HIV-associated neurocognitive disorder; Histopathology; Human; IFNAR1 gene; ISG15 gene; Impaired cognition; In Vitro; Infection; Interferon Receptor; Interferon-alpha; Interferons; Lead; Length; Mediating; Memory; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuraxis; Neuronal Dysfunction; Neurons; Pathway interactions; Phosphorylation; Play; Radial; Rattus; Reactive Oxygen Species; Regimen; Research; Role; SCID Mice; STAT1 gene; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Use Effectiveness; Viral Cancer; Viral Load result; Viral hepatitis; Water; alternative treatment; antiretroviral therapy; arm; base; cytokine; fetal; fighting; immunogenic; in vivo; insight; neurotoxic; neurotoxicity; neutralizing antibody; novel; prevent; public health relevance; receptor; stem

DESCRIPTION (provided by applicant): Interferon (IFN)a is an antiviral cytokine that has adverse effects on neuronal function. When IFNa is used as a treatment for diseases such as viral hepatitis and cancer, it can cause cognitive dysfunction if it is given in sufficient quantities and for prolonged periods. IFNa is elevated in the central nervous system (CNS) of a number of diseases associated with cognitive dysfunction, most prominently in HIV associated neurocognitive disorders (HAND). There is abundant data both in animal studies and in vitro demonstrating that IFNa is associated with neuronal dysfunction. IFNa is elevated in SCID mice with HIV encephalitis (HIVE) and is correlated with the degree of behavioral dysfunction exhibited during water radial arm maze (WRAM) testing. When HIVE mice are treated with neutralizing antibodies (NAb) to IFNa, behavioral abnormalities on WRAM testing and some aspects of HIVE histopathology are prevented or substantially reduced. To begin to understand the effects of IFNa on MAP2 expression and dendritic formation in neurons, an in vitro system using fetal rat neurons was used. These neuronal cultures reveal a dose dependent decrease in dendritic length and branching when exposed to IFNa. This effect is blocked by NAb to IFNa and partially ameliorated by NMDA antagonists. In this competitive renewal it is proposed that in vivo studies initiated during the previous grant (see above) will be extended by treating HIVE mice with a novel IFNa blocker, B18R (NormferonTM-alpha). This agent is more practical than NAb to IFNa for moving into human trials, primarily because it is less immunogenic, among other potential advantages. It appears likely that B18R crosses the blood brain barrier and inhibits CNS IFNa during encephalitis. Studies initiated in the previous granting period included the determination of effectiveness using a current combined antiretroviral therapy (cART) regimen in treating HIVE mice. These studies will also be extended by combining B18R with this cART regimen to determine if the combination is more efficacious than either alone. Importantly, these studies using both the B18R plus the cART regimen should more closely simulate human conditions, where cART reduces viral load but does not prevent HAND; therefore it is hypothesized that the two together will reduce viral load and ameliorate behavioral abnormalities in mice.. Moreover, proposed in vitro studies will extend previous in vitro results by examining the effects of IFNa on neurons to further elucidate the mechanisms of IFNa neurotoxicity. It is assumed that neurotoxicity stems from IFNa receptor (IFNaR) engagement, although previous studies mentioned above indicate that NMDA receptors also play a role. Therefore in vitro studies will determine whether IFNaR engagement correlates with downstream IFNa signaling and dendritic abnormalities. In addition, pathways involved in dendritic formation will be investigated through gene array analysis in neurons after IFNa exposure. Identification of pathways involved in the disruption of dendritic formation will contribute to understanding the basic mechanisms of memory formation and could lead to better treatments of cognitive dysfunction.

描述（由申请人提供）： 干扰素（IFN）A是对神经元功能不良影响的抗病毒细胞因子。当IFNA用作病毒肝炎和癌症等疾病的治疗方法时，如果以足够数量的时间和长时间给药，可能会导致认知功能障碍。 IFNA在许多与认知功能障碍相关的疾病的中枢神经系统（CNS）中升高，在HIV相关的神经认知障碍（手）中最为突出。动物研究和体外都有大量数据，表明IFNA与神经元功能障碍有关。 IFNA在患有HIV脑炎（HIVE）的SCID小鼠中升高，并且与水径向臂迷宫（WRAM）测试期间表现出的行为功能障碍程度相关。当蜂巢小鼠用中和抗体（NAB）治疗IFNA时，可以预防或大大降低蜂巢组织病理学的行为异常和蜂巢组织病理学的某些方面。为了开始了解IFNA对神经元中MAP2表达和树突形成的影响，使用了使用胎儿大鼠神经元的体外系统。这些神经元培养物显示出暴露于IFNA时树突状长度和分支的剂量依赖性降低。这种效应被NAB与IFNA阻塞，并被NMDA拮抗剂部分改善。 在这种竞争性更新中，建议在上一个赠款期间启动的体内研究（见上文）将通过使用新型的IFNA阻滞剂B18R（Normferontm-Alpha）来扩展蜂巢小鼠。该药物比NAB对IFNA的实用性更大，主要是因为它的免疫原性较少，并且是其他潜在的优势。 B18R似乎在脑炎期间越过血脑屏障并抑制CNS IFNA。在上一个授予期间开始的研究包括使用当前的抗逆转录病毒疗法（CART）方案确定有效性。这些研究还将通过将B18R与该购物车相结合，以确定该组合是否比单独使用更有效。重要的是，这些使用B18R加上CART方案的研究应更加紧密地模拟人类条件，在该条件下，CART会减少病毒载量，但不能阻止手。因此，假设两者一起将减少小鼠的病毒载量和改善行为异常。此外，提出的体外研究将通过检查IFNA的影响来扩展先前的体外结果 神经元进一步阐明IFNA神经毒性的机制。假定神经毒性源于IFNA受体（IFNAR）的参与度，尽管上面提到的先前的研究表明NMDA受体也起作用。因此，体外研究将确定IFNAR的参与是否与下游IFNA信号传导和树突状异常相关。此外，将通过IFNA暴露后神经元中的基因阵列分析研究参与树突形成的途径。识别与树突形成中断有关的途径将有助于理解记忆形成的基本机制，并可能导致更好地治疗认知功能障碍。