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Functional and Genomic Signatures of Escalated Fentanyl Use

芬太尼使用升级的功能和基因组特征

基本信息

批准号：
10154082
负责人：
Michael T Bardo
金额：
$ 63.07万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10154082
关键词：
Agonist Animal Behavior Animal Model Animals Astrocytes Awareness Behavior Behavior Therapy Behavioral Behavioral Model Biological Biology Biometry Brain Calcium Calcium Signaling Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chronic Clinical Clinical Research Consumption Coupled Data Databases Dependence Development Diagnosis Drug Targeting Drug usage Economic Burden Electrophysiology (science)Evaluation Family Fentanyl Genetic Databases Genetic Markers Genomics Goals Heroin Human Individual Individual Differences Intake Joints Laboratory Animals Life Link Literature Maintenance Microglia Modeling Modernization Molecular Molecular Profiling Monitor Morphine Motivation Neurobiology Neurons Nucleus Accumbens Opiate Addiction Opioid Outcome Output Patch-Clamp Techniques Pathway interactions Pattern Permeability Pharmaceutical Preparations Pharmacogenomics Pharmacology Phenotype Play Policies Population Potassium Potassium Channel Prefrontal Cortex Prevention Probability Protein Family Publishing Rattus Regulation Relapse Rewards Role Sampling Self Administration Shapes Source Statistical Models Structure Substance Use Disorder Sucrose System Testing Therapeutic Training United States National Center for Health Statistics base behavioral pharmacology behavioral phenotyping big-data science cancer therapy cell type drug abstinence fentanyl abuse functional genomics gene product genomic biomarker genomic profiles genomic signature imaging approach individual variation interdisciplinary approach medication-assisted treatment mu opioid receptors neural circuit non-drug novel novel therapeutics opioid misuse opioid mortality opioid overdose opioid use opioid use disorder opioid user personalized approach personalized cancer therapy pre-clinical reinforcer success synthetic opioid targeted treatment transcriptome sequencing transcriptomics whole genome

项目摘要

Project Summary/Abstract Misuse of opioids represents a substantial public and economic burden in the US and worldwide. The existing pharmacological approaches to treatment of opioid use disorder (OUD) are most efficacious when coupled with behavioral therapies that target individual triggers to reduce or eliminate excessive drug consumption. While individual variability in opioid use have been acknowledged repeatedly in animal behavioral models, the genomic markers linked to neurobiological adaptations underlying such variability are not well understood. We argue that understanding the molecular background of individual differences in behavioral vulnerability to opioid use is critical for development of personalized pharmacogenomic approaches for OUD that may replicate clinical success of personalized cancer treatments. In line with this argument, we hypothesize that individual behavioral variability in escalation of fentanyl use is linked to systems level variability of genomic and functional networks within in the nucleus accumbens and prefrontal cortex. Escalation of drug intake is a central component of OUD diagnosis that can be modeled in animals trained to self-administer opioids under extended access conditions. Based on the published literature and preliminary data, we propose three complementary Aims to monitor development of escalated intake at behavioral, functional cellular/network, and genomic levels of analysis. Our Aim 1 hypothesizes that escalation of fentanyl intake emerges on the background of individual differences in sensitivity to non-drug (sucrose) reward. Finding evidence to support this aim has the potential to identify vulnerable individuals prior to initiation of opioid use. Aim 2 examines neuronal outcomes associated with escalated fentanyl intake. Specifically, we will evaluate whether individual profiles of escalated intake reflect altered regulation of cell excitability by four potassium channel families and the impact on neuronal output at single cell and network levels. The data collected as part of this aim will establish functional, neuronal drivers of vulnerability to escalated intake. Finally, Aim 3 compares the genomic landscape underlying variable fentanyl escalation in laboratory animals (rats) to human opioid use databases. In this aim, we take advantage of cell-type specific RNA sequencing to evaluate both neuronal and non-neuronal mechanisms of escalated intake in the nucleus accumbens and prefrontal cortex. This aim is expected to identify novel molecular pathways linked to fentanyl escalation and test the translational relevance of our preclinical findings to a human sample. To characterize interactions at the behavioral, functional, and genomic levels of analysis, a unifying statistical framework is developed based on linear mixed models to examine the strength of bi-directional relationships between behavioral escalation of intake and molecular outcomes.

项目总结/摘要阿片类药物的滥用在美国和世界范围内构成了巨大的公共和经济负担。现有治疗阿片类药物使用障碍（OUD）的药理学方法在与行为疗法针对个体触发因素，以减少或消除过度药物消费。而在动物行为模型中，阿片类药物使用的个体差异已被反复承认，与这种变异性背后的神经生物学适应相关的基因组标记还没有很好地理解。我们认为，了解行为脆弱性个体差异的分子背景，阿片类药物的使用对于开发OUD的个性化药物基因组学方法至关重要，复制个性化癌症治疗的临床成功。根据这一论点，我们假设，芬太尼使用递增中的个体行为变异性与系统水平变异性有关，神经核和前额叶皮层内的基因组和功能网络。升级药物摄入是OUD诊断的核心组成部分，可以在训练自我给药的动物中建模阿片类药物在扩大准入条件下。根据已发表的文献和初步数据，我们建议三个互补的目标，以监测行为，功能，细胞/网络和基因组水平的分析。我们的目标1假设芬太尼摄入量的增加出现在对非药物（蔗糖）奖励的敏感性的个体差异的背景下。找到支持这一目标的证据有可能在开始使用类阿片之前查明易受伤害的个人。目的2检查与芬太尼摄入量增加相关的神经元结局。具体来说，我们将评估增加摄入量的个体曲线是否反映了四种钾离子对细胞兴奋性的调节改变通道家族以及在单细胞和网络水平上对神经元输出的影响。作为一部分收集的数据这一目标将建立功能性的，神经元驱动程序的脆弱性，以增加摄入量。第三，目标比较了实验室动物（大鼠）与人类中芬太尼递增变量的基因组格局阿片类药物使用数据库。在这个目标中，我们利用细胞类型特异性RNA测序来评估两者，神经元和非神经元的摄入量增加的机制，在脑桥核和前额皮质。这一目标预计将确定与芬太尼升级相关的新分子途径，并测试芬太尼的毒性。我们的临床前发现与人类样本的翻译相关性。为了描述在行为，功能和基因组水平的分析，一个统一的统计框架是基于线性混合模型，以检查行为升级之间的双向关系的强度，摄入量和分子结果。