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 是一种抗病毒细胞因子，对神经元功能有不利影响。当 IFNa 用于治疗病毒性肝炎和癌症等疾病时，如果服用足够量且长时间服用，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，最显着的是 HIV 相关的神经认知障碍 (HAND)。动物研究和体外研究中有大量数据表明 IFNa 与神经元功能障碍有关。 患有 HIV 脑炎 (HIVE) 的 SCID 小鼠中 IFNa 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 HIVE 小鼠接受 IFNa 中和抗体 (NAb) 治疗时，WRAM 测试和 HIVE 组织病理学某些方面的行为异常可以得到预防或显着减少。为了开始了解 IFNa 对神经元中 MAP2 表达和树突形成的影响，使用了使用胎鼠神经元的体外系统。这些神经元培养物显示，当暴露于 IFNa 时，树突长度和分支会出现剂量依赖性减少。这种作用可被 IFNa 的 NAb 阻断，并被 NMDA 拮抗剂部分改善。 在本次竞争性更新中，建议通过使用新型 IFNa 阻断剂 B18R (NormferonTM-alpha) 治疗 HIVE 小鼠来扩展上一次资助期间启动的体内研究（见上文）。这种药物比 IFNa 的 NAb 更适合进入人体试验，主要是因为它具有较低的免疫原性以及其他潜在优势。在脑炎期间，B18R 可能会穿过血脑屏障并抑制 CNS IFNa。上一授权期间启动的研究包括确定当前联合抗逆转录病毒疗法 (cART) 方案治疗 HIVE 小鼠的有效性。这些研究还将通过将 B18R 与该 cART 方案相结合来扩展，以确定该组合是否比单独使用任一方案更有效。重要的是，这些同时使用 B18R 和 cART 方案的研究应该更接近地模拟人类状况，其中 cART 可以减少病毒载量，但不能预防 HAND；因此，假设两者一起将减少病毒载量并改善小鼠的行为异常。此外，拟议的体外研究将通过检查 IFNa 对小鼠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。据推测，神经毒性源于 IFNa 受体 (IFNaR) 的参与，尽管上述先前的研究表明 NMDA 受体也发挥了作用。因此，体外研究将确定 IFNaR 参与是否与下游 IFNa 信号传导和树突异常相关。此外，将通过 IFNa 暴露后神经元的基因阵列分析来研究参与树突形成的途径。识别破坏树突形成的途径将有助于理解记忆形成的基本机制，并可能更好地治疗认知功能障碍。