Interferon-Alpha-Neurotoxicity

干扰素-α-神经毒性

• 批准号: 8822722
• 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/8822722
• 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; HIV-associated neurocognitive disorder; 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; 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）α是一种抗病毒细胞因子，其对神经元功能具有不利影响。当IFNa用于治疗病毒性肝炎和癌症等疾病时，如果给予足够的量和长时间，它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，最显著的是在HIV相关的神经认知障碍（HAND）中。在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。 IFNa在患有HIV脑炎（HIVE）的SCID小鼠中升高，并且与在水径向臂迷宫（WRAM）测试期间表现出的行为功能障碍的程度相关。当用IFNa的中和抗体（NAb）治疗HIVE小鼠时，WRAM测试中的行为异常和HIVE组织病理学的某些方面被预防或显著减少。为了开始理解IFNa对神经元中MAP 2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时树突长度和分支的剂量依赖性减少。这种作用被NAb阻断IFNa和部分改善的NMDA拮抗剂。 在这次竞争性更新中，建议通过用新型IFNa阻断剂B18 R（NormferonTM-α）治疗HIVE小鼠来扩展在先前授权期间启动的体内研究（见上文）。这种试剂比NAb到IFNa更实用，用于进入人体试验，主要是因为它的免疫原性较低，以及其他潜在的优势。B18 R似乎可能穿过血脑屏障并在脑炎期间抑制CNS IFNa。在上一个授予期启动的研究包括使用当前联合抗逆转录病毒治疗（cART）方案治疗HIVE小鼠的有效性测定。这些研究还将通过将B18 R与这种cART方案相结合来扩展，以确定组合是否比单独使用更有效。重要的是，这些使用B18 R加cART方案的研究应该更接近模拟人类条件，其中cART降低病毒载量但不能预防HAND;因此假设两者一起将降低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对细胞增殖的影响来扩展先前的体外结果。 神经元，以进一步阐明IFN α神经毒性的机制。假设神经毒性源于IFNa受体（IFNaR）的参与，尽管上述先前的研究表明NMDA受体也起作用。因此，体外研究将确定IFNaR接合是否与下游IFNa信号传导和树突异常相关。此外，将通过基因阵列分析研究IFN α暴露后神经元中树突形成的相关途径。识别参与树突形成破坏的途径将有助于理解记忆形成的基本机制，并可能导致更好的治疗认知功能障碍。