TRAFFICKING AND FUNCTION OF MU-OPIOD RECEPTOR GENETIC VARIANTS

Mu-阿片受体基因变异体的贩运和功能

• 批准号: 8570648
• 负责人: Manojkumar A Puthenveedu
• 金额: $ 20.46万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8570648
• 关键词: Absence of pain sensation; Address; Adverse effects; Adverse reactions; Affect; Agonist; Alcoholism; Biological Assay; Brain; Cell model; Cell physiology; Cells; Characteristics; Chronic; Clinical; Data; Defect; Dependence; Development; Disease; Dose; Drug Addiction; Drug abuse; Effectiveness; Endocytosis; Event; Excision; Foundations; G Protein-Coupled Receptor Genes; Gene Frequency; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Goals; Hospitals; Illicit Drugs; Image; Individual; Life; Ligands; Link; Mediating; Medicine; Molecular; Narcotic Abuses; Neurons; Opioid; Opioid Analgesics; Opioid Peptide; Pain; Pain Threshold; Pain management; Patients; Perception; Pharmaceutical Preparations; Physiological; Physiology; Population; Receptor Signaling; Regulation; Relapse; Resolution; Signal Transduction; Single Nucleotide Polymorphism; Surface; Testing; Therapeutic; United States; Variant; addiction; base; clinically relevant; combat; desensitization; design; dosage; drug of abuse; effective therapy; endogenous opioids; genetic variant; improved; insight; interest; mu opioid receptors; neuropsychiatry; novel; public health relevance; receptor; receptor function; response; socioeconomics; time use; trafficking

DESCRIPTION (provided by applicant): Opioid analgesics form the mainstay of pain management in our hospitals. However, their use is complicated by two main problems: variability in patient responses, and the development of tolerance and dependence leading to addiction. Addiction to opioids is a chronic and relapsing disorder for which there is currently no effective treatment. It is estimated that about 10% of the population in the United States is addicted to some illicit drug or other, making it a major socioeconomic problem. The main problem in addressing addiction is that we do not understand the molecular mechanisms underlying addiction. It is now established that genetic factors contribute to both these complicating aspects of opioids. The tolerance to pain, effective dosage of a defined opioid, efficacy of one drug vs. another, vulnerability to addiction, and effectiveness of addiction therapies, all depend on sequence variations that have been identified in different genes across populations. Understanding how these variations change opioid physiology in the brain will increase our understanding of pain and addiction, help in the development of new treatments for both these problems, and provide key steps in advancing personalized medicine. One key gene where genetic variations have been identified is OPRM1, which encodes the mu-opioid receptor (MOR), the target of many clinically abused drugs. Studies have linked prevalent single nucleotide polymorphisms in MOR to variations in pain tolerance, analgesia, vulnerability to opioid tolerance and dependence, alcoholism, and neuropsychiatric disorders. Importantly, whether and how these polymorphisms change MOR function at a molecular level is not known. We propose to use our expertise in developing high-resolution imaging assays to study GPCR trafficking in living cells to study how prevalent MOR polymorphisms change MOR function in neurons. The SNPs will be prioritized based on the known allelic frequency and linkage to clinical disorders, starting with A118G, the most prevalent and clinically relevant SNP. Specifically, we will test activation-induced signaling and trafficking of MOR - two fundamental events that define MOR function in neurons. Completion of this study will give us a better understanding of the normal variation of opioid signaling in physiologically relevant neurons, provide insights into functional selectivity of clinically relevant drugs, and help in developing o a platform to develop personalized doses and strategies for pain therapy and management of drug addiction.

描述（由申请人提供）：阿片类镇痛药构成了我们医院疼痛管理的支柱。但是，它们的使用使两个主要问题变得复杂：患者反应的变异性以及耐受性和依赖性导致成瘾的发展。对阿片类药物的成瘾是一种慢性疾病，目前没有 有效的治疗。据估计，美国约有10％的人口沉迷于某些非法药物或其他药物，这使其成为一个主要的社会经济问题。解决成瘾的主要问题是我们不了解成瘾的分子机制。现在已经确定遗传因素有助于阿片类药物的这两个复杂方面。对疼痛的耐受性，有效的阿片类药物的有效剂量，一种药物与另一种药物的功效，对成瘾的脆弱性以及成瘾疗法的有效性，都取决于在种群中不同基因中鉴定出的序列变化。了解这些变化如何改变大脑中的阿片类药物生理学将增加我们对疼痛和成瘾的理解，帮助为这两种问题开发新的治疗方法，并提供推进个性化医学的关键步骤。已经鉴定出遗传变异的一个关键基因是OPRM1，该基因编码MU-阿片受体（MOR），这是许多临床滥用药物的靶标。研究已将MOR中普遍的单核苷酸多态性与疼痛耐受性，镇痛，阿片类药物耐受性和依赖性，酒精中毒和神经精神疾病的脆弱性的变化联系起来。重要的是，这些多态性是否以及如何在分子水平上改变MOR功能。我们建议利用我们的专业知识来开发高分辨率成像测定法来研究活细胞中的GPCR运输，以研究神经元中普遍的MOR多态性改变MOR的功能。 SNP将根据已知的等位基因频率和与临床疾病的联系确定优先级，从A118G开始，这是最普遍和最相关的SNP。具体而言，我们将测试激活诱导的MOR信号传导和运输 - 两个定义神经元功能的基本事件。这项研究的完成将使我们更好地了解生理上相关神经元中阿片类药物信号的正常变化，提供有关临床相关药物功能选择性的见解，并有助于开发一个平台，以开发针对药物成瘾的疼痛治疗和管理的个性化剂量和策略。