Using Phage Display to Identify Novel Peptide Modulators of Ethanol Targets

使用噬菌体展示来识别乙醇靶标的新型肽调节剂

• 批准号: 8134745
• 负责人: Megan E. Tipps
• 金额: $ 1.43万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134745
• 关键词: Acetylcholine; Affect; Affinity; Alcohol consumption; Alcoholism; Alcohols; Bacteriophages; Behavioral; Benzodiazepines; Binding; Biochemical; Cell Surface Proteins; Cells; Complex; Development; Enzymes; Ethanol; Family; Family member; Future; Gated Ion Channel; Glycine Receptor Binding; Glycine Receptors; Goals; Individual; Ion Channel; Knock-in Mouse; Knock-out; Libraries; Ligands; Mediating; Mediator of activation protein; Methods; Nature; Neurotransmitter Receptor; Pathway interactions; Peptides; Phage Display; Pharmaceutical Preparations; Phenotype; Physiological; Play; Procedures; Property; Proteins; Research; Research Personnel; Role; Serotonin Receptors 5-HT-3; Simulate; Specificity; System; Technology; Testing; Work; Xenopus oocyte; acamprosate; addiction; alcohol behavior; alcohol effect; alcohol response; alcoholism therapy; base; combat; design; drug development; drug discovery; drug of abuse; gamma-Aminobutyric Acid; high throughput screening; in vivo; interest; member; molecular site; neuronal excitability; neurophysiology; neurotransmission; novel; receptor; receptor function; research study; small molecule; success

DESCRIPTION (provided by applicant): Ethanol is a wildly used drug of abuse with a complex and poorly understood mechanism of action. A major hurdle in understanding the mechanism of alcohol action is the large number of putative ethanol targets. While many cellular components are known to be effected by alcohol, the contributions of each target to the overall physiological and behavioral effects of alcohol are unknown. We propose a method for isolating the effects of ethanol at a single target without altering the wild-type system. We plan to utilize phage display technology to identify peptides that bind with high specificity at a single putative ethanol target, the glycine receptor (GlyR). These peptides will then be tested electrophysiologically for modulatory effects on the GlyR. The goal of the proposed work is to identify peptides that either mimic or antagonize the effects of ethanol on the GlyR without affecting other ethanol targets. The long term objective of this project is to isolate the contribution of individual putative ethanol targets by identifying highly selective small peptides that either mimic or antagonize the effects of ethanol at a single target. Peptides that mimic ethanol actions at a single target would allow researchers to simulate the application of ethanol to only that target. Conversely, co-application of a highly specific ethanol antagonist and ethanol would simulate the effects of ethanol on every target except the selected one. Essentially, the effects of ethanol on a single target could be isolated without disturbing the overall system. In this way, the role of the individual target plays in the expression of ethanol's effects could be identified. Understanding the importance of individual targets to ethanol consumption, addiction and behavioral effects will allow for the rational, targeted development of drugs to combat alcoholism.

描述（由申请人提供）：乙醇是一种滥用的疯狂药物，具有复杂且知之甚少的作用机理。理解酒精作用机理的主要障碍是大量推定的乙醇靶标。虽然已知许多细胞成分受酒精影响，但每个靶标对酒精的总体生理和行为影响的贡献尚不清楚。我们提出了一种在不改变野生型系统的情况下隔离乙醇在单个靶标上的作用的方法。我们计划利用噬菌体显示技术来鉴定在单个推定的乙醇靶标，甘氨酸受体（GLYR）上与高特异性结合的肽。然后，将对这些肽进行电生理测试，以实现对Glyr的调节作用。拟议工作的目的是确定模仿或拮抗乙醇对Glyr的影响而不会影响其他乙醇靶标的肽。该项目的长期目标是通过识别高度选择性的小肽来隔离单个推定乙醇靶标的贡献，以模仿或对抗单个靶标的乙醇的作用。模拟单个靶标的乙醇作用的肽将使研究人员仅模拟乙醇在该靶标上的应用。相反，高度特异性乙醇拮抗剂和乙醇的共同应用将模拟乙醇对除选定靶标除外的每个靶标的作用。本质上，可以在不干扰整体系统的情况下隔离乙醇对单个靶标的影响。这样，可以确定单个目标在乙醇作用表达中的作用。了解各个靶标对乙醇消耗，成瘾和行为影响的重要性将使毒品的有针对性开发以对抗酒精中毒。