Serum Biomarkers of Alcohol Self-Administration in Non-Human Primates

非人类灵长类动物自我饮酒的血清生物标志物

• 批准号: 7187483
• 负责人: KENT E VRANA
• 金额: $ 35.71万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7187483
• 关键词: Acute; Address; Adolescent; Adult; Albumins; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Animals; Archives; Biological; Biological Assay; Biological Markers; Blinded; Clinical; Cluster Analysis; Data; Diagnosis; Diagnostic; Diagnostic Sensitivity; Diet; Disease; Dose; Drug usage; Enzyme-Linked Immunosorbent Assay; Enzymes; Ethanol; Female Adolescents; Fluorescence; Funding; General Population; Goals; Haptoglobins; Health; Heavy Drinking; Human; Immunoblotting; Immunoglobulins; Individual; Institution; Intake; Interdisciplinary Study; Life; Measurement; Medical Surveillance; Methods; Modeling; Monkeys; Pathology; Pattern; Population; Predictive Value; Pregnancy; Probability; Process; Productivity; Protein C Inhibitor; Proteins; Proteomics; Recording of previous events; Relapse; Research Personnel; Resources; Risk; Sampling; Score; Screening procedure; Self Administration; Self-Administered; Sensitivity and Specificity; Serum; Serum Proteins; Source; Specificity; Study Subject; Talents; Testing; Training; Transferrin; Two-Dimensional Gel Electrophoresis; Validation; alcoholism/alcohol abuse; animal resource; behavior observation; chronic alcohol ingestion; cohort; design; drinking; gel electrophoresis; health care delivery; high risk drinking; indexing; male; nonhuman primate; problem drinker; protein expression; research clinical testing; research study; tool

DESCRIPTION (provided by applicant): Ethanol abuse and alcoholism remain very serious societal problems. A significant problem is the inability to diagnose alcohol abuse either in the general population or within selected groups of individuals such as adolescents and the recovering alcoholic. Accordingly, this proposal seeks to develop diagnostic biomarker signatures of acute and chronic alcohol consumption for diagnosing high-risk drinking, detecting relapse to drinking, disclosing recent drinking and in high risk situations such as pregnancy. To this end, studies are proposed to examine serum proteins and protein patterns for potential signatures in a powerful non-human primate model that is not encumbered by problems of comorbid drug use, inadequate diet and unreliable assessments of drinking history. In these NIAAA-funded, ongoing, within-subject studies, monkeys have been induced to voluntarily drink large amounts of alcohol. In the course of the studies (encompassing over 100 individual animals covering years of behavior and observation), serum samples have routinely been collected and archived. Experiments are proposed to screen these samples for potential biomarkers that can then be taken forward into the human population. Serum samples from a long-standing nonhuman primate self-administration study will be used as a training set for biomarker identification using high throughput proteomics. Samples will be processed to deplete the most abundant, obscuring proteins and then subjected to 2-DIGE (2-D Fluorescence Difference In-Gel Electrophoresis) for quantitative fluorescence identification of altered serum protein expression followed by MALDI-ToF/ToF identification of protein species. Statistical validation will be conducted, in a blinded fashion, using a test set of samples from an independent colony of self-administering monkeys, which will also contain data on adolescent vulnerability. The key criteria of any putative biomarkers will be sensitivity (percentage of positive scores among drinkers) and specificity (percentage of false positives in a non-drinking population). In addition, these studies will provide initial indices of positive and negative predictive values for biomarker signatures. A clinical test for ethanol abuse and alcoholism would have many potential uses. To discover protein biomarkers of ethanol abuse and alcoholism, serum from a controlled non-human primate population self- administering ethanol will be examined by quantitative proteomic methods.

描述（由申请人提供）：乙醇滥用和酗酒仍然是非常严重的社会问题。一个重要的问题是无法诊断普通人群或特定人群（例如青少年和戒酒者）的酒精滥用情况。因此，该提案旨在开发急性和慢性饮酒的诊断生物标志物特征，用于诊断高风险饮酒、检测饮酒复发、披露近期饮酒情况以及怀孕等高风险情况。为此，建议研究在强大的非人类灵长类动物模型中检查血清蛋白和蛋白质模式的潜在特征，该模型不受共病药物使用、饮食不足和饮酒史评估不可靠等问题的阻碍。在这些由 NIAAA 资助、正在进行的受试者内研究中，猴子被诱导自愿饮用大量酒精。在研究过程中（涵盖 100 多只动物个体，涵盖多年的行为和观察），血清样本已被例行收集和存档。建议进行实验来筛选这些样本中潜在的生物标志物，然后将其应用于人群。来自长期非人类灵长类自我给药研究的血清样本将用作使用高通量蛋白质组学识别生物标志物的训练集。对样品进行处理以去除最丰富的模糊蛋白质，然后进行 2-DIGE（二维荧光差异凝胶电泳），以定量荧光鉴定改变的血清蛋白表达，然后进行 MALDI-ToF/ToF 鉴定蛋白质种类。将以盲法方式进行统计验证，使用来自独立的自我管理猴子群的测试样本集，其中还将包含青少年脆弱性的数据。任何假定的生物标志物的关键标准都是敏感性（饮酒者中阳性得分的百分比）和特异性（非饮酒人群中假阳性的百分比）。此外，这些研究将为生物标志物特征提供阳性和阴性预测值的初始指数。针对乙醇滥用和酗酒的临床测试将有许多潜在用途。为了发现乙醇滥用和酗酒的蛋白质生物标志物，将通过定量蛋白质组学方法检查来自自我施用乙醇的受控非人类灵长类动物群体的血清。