Alcohol dependence and HCV: mechanisms of combined CNS injury

酒精依赖与丙型肝炎：中枢神经系统联合损伤的机制

• 批准号: 9275388
• 负责人: JENNIFER M LOFTIS
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 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/9275388
• 关键词: Abstinence; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Animal Model; Antigens; Antiviral Agents; Antiviral Therapy; Anxiety; Behavior; Behavioral; Biological; Blood; Blood - brain barrier anatomy; Blood specimen; Brain; Brain Injuries; Brain region; Breathalyzer Tests; CD8 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Central Nervous System Infections; Chronic; Chronic Hepatitis C; Cognitive; Cognitive deficits; Comorbidity; Consumption; Data; Disease remission; Enzymes; Ethanol; Extrahepatic; Frequencies; Funding; Future; Goals; Healthcare Systems; Heavy Drinking; Hepatitis C; Histologic; Human; Immune; Immunoassay; Immunologics; Immunotherapeutic agent; Impaired cognition; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-2; Laboratories; Liver; Lymphocytic choriomeningitis virus; Measures; Mediating; Medical center; Mental Depression; Methamphetamine dependence; Migration Inhibitory Factor; Modeling; Molecular; Mus; Nerve Degeneration; Neuraxis; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Plasma; Play; Population; Prevalence; Recruitment Activity; Relapse; Research Project Grants; Risk; Role; Sampling; Specimen; Spleen; Study models; Substance abuse problem; Sucrose; Surface; Syndrome; Systemic disease; T cell response; T-Lymphocyte; TNF gene; Testing; Time; Translational Research; Treatment outcome; Variant; Veterans; Viral; Viral Load result; Virus Diseases; addiction; alcohol effect; alcohol exposure; alcohol relapse; alcohol risk; alcohol use disorder; behavior test; central nervous system injury; chemokine; chronic alcohol ingestion; cognitive function; cytokine; depressive symptoms; disturbance in affect; drug of abuse; immune activation; immunopathology; immunoreactivity; improved; insight; intravenous injection; liver injury; mouse model; multi-site trial; neuroinflammation; neuropsychiatry; novel; object recognition; phenylpyruvate tautomerase; pre-clinical; preference; public health relevance; relapse risk; research clinical testing; successful intervention; therapeutic development; treatment group; treatment trial

DESCRIPTION (provided by applicant): PROJECT SUMMARY One of the major consequences of chronic alcohol use in brain is increased inflammation that leads to neurodegeneration with associated cognitive and psychiatric impairments. Neuropsychiatric impairments persist in patients following substance abuse and are associated with poorer treatment outcomes. HCV is also associated with a variety of extrahepatic syndromes, including central nervous system (CNS) damage and neuropsychiatric impairments. However, it is unclear whether such cognitive and mood disturbances are a function of systemic disease, damaged hepatic function, or virus infection of the CNS. Animal models are needed to provide new insights into the molecular mechanisms and pathways affected by co-morbid alcohol dependence and chronic viral infection, and also those which are responsible for the persistence of neuropsychiatric impairments following abstinence and viral clearance. Our overall hypothesis is that HCV patients with co-morbid AUDs are at increased risk of brain damage that contributes to alcohol relapse risk. In humans and across species, our goal is to identify specific mechanisms by which chronic viral infection and alcohol induce abnormalities in immune cell function and contribute to persistent neuropsychiatric impairments. The following specific aims are proposed: 1) Determine the effects of HCV and alcohol use on peripheral T cell response and psychiatric function in veterans with co-morbid HCV and AUDs. Biological specimens and psychiatric data will be derived from those currently being collected for a treatment trial in veterans with HCV and co-morbid AUDs. We will obtain peripheral blood mononuclear cells and evaluate them across time for: i) phenotypic changes in T-cell populations, ii) surface and intracellular accumulation of cytokines, and iii) immunoreactivity to neuroantigens and other antigens. Blood samples will be used to measure key cytokines and chemokines, viral load, and liver enzymes. Rating scales that measure depression, anxiety, and alcohol consumption will also be used. Results from the immunoassays will be analyzed in relation to psychiatric measures, viral load, and alcohol use, as well as in relation to the findings from Aim 2. 2) Investigate the role of chronic alcohol exposure in regulating peripheral and central T-cell responses, CNS immunopathology, and behavioral signs of anxiety, depression, and cognitive impairments in mice infected with lymphocytic choriomeningitis virus (LCMV, clone 13 variant), an established model for HCV infections in humans. Mice will be chronically exposed to and dependent on ethanol administered intragastrically followed by intravenous injection of LCMV (or vehicle) to evaluate the consequences of co-morbidity. Behavioral tests will be conducted following ethanol exposure to assess anxiety, depressive-like behavior, and cognitive function. Blood, brain, and spleen samples will be collected to: i) measure blood ethanol concentrations, liver enzymes, viral titers, and key cytokines and chemokines, ii) evaluate T cell frequencies, including LCMV-specific CD8+ T cells (utilizing tetramer analysis; H-2Ld-restricted NP118), iii) calculate the percentage of CD4+, CD8+, and antigen-specific CD8+ T cells producing key cytokines (e.g., TNF- ), iv) evaluate immunoreactivity to neuroantigens, and v) assess neuroinflammation and neuronal degeneration. Examining the role of alcohol in regulating viral persistence and CNS immunopathology in LCMV-infected mice will lead to a more comprehensive understanding of co-morbid AUDs and HCV and may identify targets for future therapeutic development. If our hypotheses are supported, future studies will test our immunotherapeutic strategy that we have found reduces neuroinflammation and improves cognitive function in mouse models of methamphetamine dependence. Interventions that successfully treat alcohol induced neuropsychiatric impairments have a high likelihood of also reducing relapse rates and improving treatment outcomes.

描述（由申请人提供）： 项目摘要在​​大脑中使用慢性酒精的主要后果之一是炎症增加，导致神经退行性与相关的认知和精神障碍。药物滥用后患者的神经精神障碍持续存在，并且与治疗结果较差有关。 HCV还与各种肝外综合症有关，包括中枢神经系统（CNS）损害和神经精神障碍。但是，尚不清楚这种认知和情绪障碍是全身性疾病，肝功能受损或中枢神经系统病毒感染的功能。需要动物模型来提供有关受到合并酒精依赖性和慢性病毒感染影响的分子机制和途径的新见解，以及那些在戒酒和病毒清除后导致神经精神障碍持续性的持续性。我们的总体假设是，HCV auds患者的脑损伤风险增加，导致酒精复发风险。在人类和整个物种中，我们的目标是确定慢性病毒感染和酒精诱导免疫细胞功能异常的特定机制，并导致持续的神经精神障碍。提出了以下具体目的：1）确定与hcv和auds的退伍军人对HCV和酒精使用对外周T细胞反应和精神病功能的影响。生物标本和精神病数据将源自当前正在接受HCV和合并AUDS的退伍军人的治疗试验的标本。我们将获得外周血单核细胞，并在时间上评估它们的时间：i）T细胞种群的表型变化，ii）细胞因子的表面和细胞内积累，以及iii）对神经抗原和其他抗原的免疫反应性。血样将用于测量关键的细胞因子和趋化因子，病毒载量和肝酶。还将使用测量抑郁症，焦虑和饮酒的评级量表。免疫测定的结果将与精神病措施，病毒负荷和饮酒有关，以及与目标的发现有关2。2）研究慢性酒精暴露在调节周围和中央T-CELL反应中的作用病毒（LCMV，克隆13变体），这是人类HCV感染的已建立模型。小鼠将长期暴露于术后施用的乙醇，然后静脉注射LCMV（或媒介物），以评估合并症的后果。乙醇暴露后将进行行为测试，以评估焦虑，抑郁样行为和认知功能。 Blood, brain, and spleen samples will be collected to: i) measure blood ethanol concentrations, liver enzymes, viral titers, and key cytokines and chemokines, ii) evaluate T cell frequencies, including LCMV-specific CD8+ T cells (utilizing tetramer analysis; H-2Ld-restricted NP118), iii) calculate the percentage of CD4+, CD8+, and antigen-specific CD8+ T细胞产生关键细胞因子（例如TNF-），iv）评估对神经抗原的免疫反应性，V）评估神经炎症和神经元变性。检查酒精在调节病毒持久性和CNS免疫病理学在LCMV感染的小鼠中的作用将导致对合并AUDS和HCV的更全面了解，并可能确定未来治疗性发育的目标。如果支持我们的假设，未来的研究将测试我们的免疫治疗策略，我们发现我们发现神经炎症会减少并改善甲基苯丙胺依赖性小鼠模型中的认知功能。成功治疗酒精诱发的神经精神障碍的干预措施也很有可能降低复发率并改善治疗结果。