Interferon-Alpha-Neurotoxicity

干扰素-α-神经毒性

• 批准号: 8541199
• 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/8541199
• 关键词: A Mouse; 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; Histopathology; Human; IFNAR1 gene; Impaired cognition; In Vitro; Infection; Interferon Receptor; Interferon-alpha; Interferons; Lead; Length; Mediating; Memory; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuraxis; Neurocognitive; Neuronal Dysfunction; Neurons; Pathway interactions; Phosphorylation; Play; Radial; Rattus; Reactive Oxygen Species; Regimen; Research; Role; SCID Mice; STAT1 gene; Signal Pathway; Signal Transduction; Simulate; 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)： 干扰素是一种对神经功能有不良影响的抗病毒细胞因子。当IFNA用于治疗病毒性肝炎和癌症等疾病时，如果剂量足够且持续时间较长，可能会导致认知功能障碍。在许多与认知功能障碍相关的疾病中，IFNA在中枢神经系统(CNS)中升高，尤其是在HIV相关性神经认知障碍(HAND)中。在动物实验和体外实验中都有大量数据表明，IFNA与神经元功能障碍有关。在患有HIV脑炎(HIVE)的SCID小鼠中，IFNA水平升高，并与在水径向臂迷宫(WRAM)测试中表现出的行为障碍的程度有关。当用IFNA中和抗体(NAB)治疗蜂箱小鼠时，Wram测试的行为异常和蜂箱组织病理学的某些方面被预防或显著减少。为了开始了解IFNA对神经元MAP2表达和树突状细胞形成的影响，我们使用了一个使用胎鼠神经元的体外系统。这些神经元培养显示，当暴露于IFNA时，树突状细胞的长度和分支呈剂量依赖性的减少。此作用可被NAB拮抗IFNA，并被NMDA拮抗剂部分改善。在这次竞争性更新中，有人提议，在上一次拨款(见上文)期间启动的体内研究将通过使用新型IFNA阻滞剂B18R(NormferonTM-Alpha)治疗蜂巢小鼠来延长。在进入人体试验方面，这种试剂比IFNA的NAB更实用，主要是因为它的免疫原性较低，以及其他潜在优势。在脑炎期间，B18R很可能穿过血脑屏障，抑制CNS IFNA。在前一批授权期启动的研究包括使用当前联合抗逆转录病毒疗法(CART)治疗蜂巢小鼠的有效性的确定。这些研究还将通过将B18R与这种CART方案联合使用来扩展，以确定联合治疗是否比单独使用更有效。重要的是，这些使用B18R和CART方案的研究应该更接近模拟人类的条件，在CART方案中，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，拟议的体外研究将扩展先前的体外结果，检查IFNA对 以进一步阐明IFNA的神经毒性机制。神经毒性被认为源于IFNA受体(IFNaR)的参与，尽管前面提到的研究表明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信号和树突异常相关。此外，在IFNA暴露后，将通过神经元中的基因阵列分析来研究参与树突形成的途径。识别参与破坏树突形成的途径将有助于理解记忆形成的基本机制，并可能导致更好的认知功能障碍的治疗。