Dynamic Mechanisms of GPCRs Targeted by Drugs of Abuse

滥用药物靶向 GPCR 的动态机制

基本信息

批准号：
8871703
负责人：
Marta Filizola
金额：
$ 37.57万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8871703
关键词：
Adverse effects Agonist Analgesics Applications Grants Behavioral Binding Biophysics Cell membrane Cereals Collaborations Crime Data Development Drug Addiction Drug abuse Ensure Environment Equilibrium Family Funding Future G-Protein-Coupled Receptors Goals Health Homo In Vitro Laboratories Lead Letters Ligand Binding Ligands Literature Management Information Systems Measurable Mediating Membrane Modeling Molecular Molecular Conformation Molecular Models Opioid Pathway interactions Pharmaceutical Preparations Phenotype Phosphorylation Physiological Plague Productivity Proteins Public Health Receptor Signaling Research Resolution Role Scientist Signal Transduction Societies Structure Suggestion System Techniques Therapeutic United States Validation Work addiction base cost desensitization drug of abuse in vivo insight knowledge base member molecular dynamics molecular modeling mu opioid receptors novel therapeutics opioid abuse protein protein interaction receptor receptor binding receptor function research study response screening structural biology theories trafficking virtual web interface

项目摘要

DESCRIPTION (provided by applicant): With over 2 million people in the United States alone known to abuse opioid-based pain medications, addiction to these drugs represents a significant public health concern. The mu-opioid receptor (MOR) is the member of the G protein-coupled receptor (GPCR) family that primarily mediates the actions of clinically used opioid- based analgesics. Based on extensive in vitro and in vivo work over the past decades, it has become increasingly clear that opioid ligands can produce different signaling, phosphorylation, desensitization, and internalization of MOR, with major implications for its physiological responses, including the development of analgesic tolerance. The recent suggestion that MOR oligomerization can modulate receptor binding, signaling, and/or trafficking further complicates our understanding of MOR-mediated function. The overall goal of the research proposed in this application is to reveal the molecular mechanisms underlying the observed functional selectivity at MOR. This information is important to ensure the fine-tuning of MOR signaling towards desired therapeutic pathways but away from those mediating adverse side effects, with the ultimate goal of discovering non-addictive analgesic agents. The computational research proposed in this grant application takes advantage of cutting-edge developments in theory and experiments to obtain rigorous mechanistic insight, at an unprecedented level of molecular detail, into the structure, spatio-temporal organization, and dynamics of MOR in the membrane, thus broadening current understanding of MOR biased agonism. Specifically, we will contribute structural and dynamic information regarding sparsely-populated states of MOR that are currently impossible or difficult to retrieve experimentally, thereby generating testable hypotheses of how, at the molecular level, different opioids induce differential oligomerization and signaling of MOR, leading to the specific behavioral effects of the drugs. Experimental validation of these computational predictions, to be attained through collaborations with independently funded laboratories, will advance our current understanding of fundamental basic mechanisms of MOR function, and pave the way to novel therapeutic strategies against drug abuse and addiction. The data that will emerge from this application will be added to other relevant recent information on GPCR oligomerization, and further populate our recently deployed GPCR-Oligomerization Knowledge Base system to continue to promote and support productive collaborations between computational and experimental scientists working on GPCRs involved in drug abuse.

描述（由申请人提供）：仅在美国，就有超过200万人滥用基于阿片类药物的止痛药的人，对这些药物的成瘾是一个重大的公共健康问题。 MU-阿片受体（MOR）是G蛋白偶联受体（GPCR）家族的成员，该家族主要介导临床使用的基于阿片类药物的镇痛药的作用。基于过去几十年来广泛的体外和体内工作，越来越清楚的是，阿片类药物可以产生不同的信号传导，磷酸化，脱敏和MOR的内在化，这对其生理反应产生了重大影响，包括其生理反应，包括镇痛耐受性的发展。最近关于MOR寡聚可以调节受体结合，信号传导和/或运输的建议使我们对MOR介导的功能的理解更加复杂。本应用中提出的研究的总体目标是揭示MOR处观察到的功能选择性的分子机制。该信息对于确保MOR信号传导向所需的治疗途径进行微调很重要，但要远离那些介导的不良副作用，最终目的是发现非添加性镇痛药。本赠款应用中提出的计算研究利用了理论和实验中的最先进的发展，以实现的分子细节水平获得严格的机械洞察力，以膜的结构，时空组织和MOR在膜中的动态，从而扩大了对MOR偏见的激动主义偏见的人的MOR的动态。具体而言，我们将提供有关目前不可能或难以在实验上检索的稀疏填充状态的结构和动态信息，从而产生可检验的假设，即在分子水平上，不同的阿片类药物如何诱导MOR的不同阿片类药物，从而导致药物的特定行为影响。通过与独立资助的实验室的合作来实现这些计算预测的实验验证，将促进我们当前对MOR功能的基本基本机制的理解，并为针对药物滥用和成瘾的新型治疗策略铺平道路。该应用程序将出现的数据将添加到有关GPCR寡聚化的其他相关信息中，并进一步填充了我们最近部署的GPCR-Oligomerization知识基础系统，以继续促进和支持从事药物滥用GPCR的计算和实验科学家之间的生产性合作。