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）：乙醇是一种被广泛滥用的药物，其作用机制复杂且知之甚少。理解酒精作用机制的一个主要障碍是大量假定的乙醇靶点。虽然已知许多细胞成分受到酒精的影响，但每个目标对酒精的整体生理和行为影响的贡献尚不清楚。我们提出了一种方法，在不改变野生型系统的情况下，在单个目标上分离乙醇的影响。我们计划利用噬菌体展示技术来鉴定具有高特异性结合单一乙醇靶点甘氨酸受体（GlyR）的肽。这些肽将被电生理学测试对GlyR的调节作用。提出的工作的目标是确定肽要么模仿或拮抗乙醇对GlyR的影响，而不影响其他乙醇目标。该项目的长期目标是通过鉴定高选择性的小肽来分离单个假定的乙醇靶点的贡献，这些小肽要么模仿乙醇的作用，要么在单个靶点上拮抗乙醇的作用。模拟乙醇作用于单一目标的肽将使研究人员能够模拟乙醇仅作用于该目标的应用。相反，高度特异性的乙醇拮抗剂和乙醇的共同应用将模拟乙醇对除选定目标外的每个目标的影响。从本质上讲，乙醇对单个目标的影响可以在不干扰整个系统的情况下被分离出来。通过这种方式，个体靶标在乙醇效应表达中所起的作用可以被确定。了解个体目标对乙醇消费、成瘾和行为影响的重要性，将有助于合理、有针对性地开发对抗酒精中毒的药物。