A transgenic model of opioid tolerance and drug discovery

阿片类药物耐受性和药物发现的转基因模型

• 批准号: 8987025
• 负责人: Brock Grill
• 金额: $ 24万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8987025
• 关键词: Addictive Analgesics; Address; Adverse effects; Agonist; American; Analgesics; Animal Behavior; Animal Model; Animals; Behavior; Behavioral; Behavioral Assay; Biochemistry; Biological; Biological Assay; Biological Models; Biology; Caenorhabditis elegans; Cells; Chemicals; Cocaine; Codeine; Data; Dependence; Development; Drug Addiction; Drug Targeting; Environment; Enzymes; Exposure to; Fentanyl; Figs - dietary; Funding Mechanisms; Future; G Protein-Coupled Receptor Signaling; G protein coupled receptor kinase; G-Protein-Coupled Receptors; Generations; Genes; Genetic Models; Genetic Screening; Goals; Heterotrimeric GTP-Binding Proteins; Homeostasis; Human; Hyperalgesia; Ion Channel; Lead; Life; Link; Locomotion; Mediating; Medical; Medicine; Methamphetamine; Microscopic; Modeling; Molecular Target; Monitor; Morphine; Movement; Nematoda; Nervous system structure; Neurons; Nicotine; Nociception; Opioid; Opioid Receptor; Organism; Oxycodone; Pain; Pharmaceutical Preparations; Pharmacologic Substance; Problem Solving; Property; Reaction; Receptor Signaling; Regulator Genes; Research; Second Messenger Systems; Series; Signal Transduction; Site; Societies; Solutions; Study models; System; Transgenic Animals; Transgenic Model; Transgenic Organisms; Work; addiction; attenuation; base; behavioral response; behavioral tolerance; chronic pain; clinical practice; desensitization; drug discovery; genetic approach; in vivo; innovation; insight; neural circuit; neuronal circuitry; novel; prevent; programs; promoter; public health relevance; receptor; response; screening; second messenger; small molecule; stem; success

 DESCRIPTION (provided by applicant): Opioid drugs are the most widely used analgesics in medicine, and are also some of the most widely abused substances. Tolerance to opioids is a major medical problem resulting in reduced efficacy of these compounds for treatment of chronic pain, and increasing the potential for addiction and abuse. In this proposal, we detail an innovative, potentially transformative approach to reveal insight into the mechanisms of opioid tolerance, and propose to develop a humanized, transgenic platform for discovery of small molecules that block or reduce tolerance. Our approach aims to find drugs and drug targets that block tolerance, thereby greatly increasing the efficacy of existing blockbuster pharmaceuticals. Blocking or reducing tolerance to opioids would also be a major step towards preventing dependence. We propose to use the nematode, C. elegans, as a genetic model system to study signaling by a G protein coupled receptor (GPCR) that mediates analgesic and addictive responses to opioids, the µ-opioid receptor (MOR). We will generate transgenic C. elegans that express human MOR and respond to its stimulation by opioids with behavioral changes. By using a series of cell-specific promoters, we propose to analyze two major types of behavior: chemosensation and locomotion. Further, we will develop assays to study behavioral tolerance caused by prolonged exposure to MOR agonists. In this proposal, we take aim at developing a humanized, transgenic platform to study opioid-induced tolerance with the potential to provide significant and unbiased insight into the mechanisms of tolerance and its chemical attenuation. Because our proposal lets the biology of a living organism provide a solution to the problem of tolerance, our approach is a significant advance over previous efforts that have focused on specific molecular targets using cell-based assays that have, unfortunately, had limited success. The microscopic size of C. elegans and the scalability of the assays we propose to develop are simply not possible in mammalian or vertebrate whole organismal systems further supporting our choice of model system. The successful implementation of our proposal has the potential to be transformative to how drug addiction is studied. Successful implementation of this proposal will lay the ground for the discovery of novel small molecules and genes that regulator of tolerance. The success of our work will encourage the development of humanized C. elegans high throughput behavioral platforms for many other addiction targets including cocaine, methamphetamine, and nicotine.

 描述（由适用提供）：阿片类药物是医学中最广泛使用的镇痛药，也是一些最广泛的滥用物质。对阿片类药物的耐受性是一个主要的医学问题，导致这些化合物治疗慢性疼痛的效率降低，并增加成瘾和滥用的可能性。在此提案中，我们详细介绍了一种创新的，潜在的变革性方法，以揭示对阿片类药物耐受性机制的见解，并提出开发人性化的转基因平台，以发现可阻止或降低耐受性的小分子。我们的方法旨在找到阻断耐受性的药物和药物靶标，从而大大提高现有大片药物的效率。阻止或降低对阿片类药物的耐受性也将是防止依赖性的主要步骤。我们建议将线虫C. exemans用作遗传模型系统，以通过G蛋白偶联接收器（GPCR）研究信号，从而介导对阿片类药物的镇痛和添加剂反应，µ-阿片类受体（MOR）。我们将生成转基因秀丽隐杆线虫，以表达人类的MOR并应对行为变化的阿片类药物的刺激。通过使用一系列细胞特异性启动子，我们建议分析两种主要类型的行为：化学敏化和运动。此外，我们将开发用于研究长期暴露于MOR激动剂引起的行为耐受性的测定。在此提案中，我们旨在开发一个人源化的转基因平台来研究阿片类药物诱导的耐受性，并有可能对耐受性及其化学衰减机制提供重要的无偏见。因为我们的建议使生物体的生物学为耐受性问题提供了解决方案，所以我们的方法是对以前的努力的重大进步，这种努力使用基于细胞的测定方法，而这些分子使用基于细胞的测定，但不幸的是，成功的成功。在哺乳动物或脊椎动物的整个有机体系统中，根本不可能提供秀丽隐杆线虫的显微镜大小以及我们提出的暗示的可扩展性，从而进一步支持了我们选择模型系统的选择。我们提案的成功实施有可能对研究吸毒成瘾的方式进行变革。该提案的成功实施将为发现新型的小分子和调节耐受性的基因奠定基础。我们工作的成功将鼓励为可卡因，甲基苯丙胺和尼古丁在内的许多其他添加目标开发人性化的秀丽隐杆线虫高通量行为平台。