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：
10549836
负责人：
Michael T Bardo
金额：
$ 65.72万
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/10549836
关键词：
Acceleration Animal Behavior Animal Model Animals Astrocytes Awareness Behavior Behavior Therapy Behavioral Behavioral Model Biology Biometry Brain Calcium Calcium Signaling Cells 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 Opioid Receptor Outcome Output Patch-Clamp Techniques Pathway interactions Pattern Permeability Persons Pharmaceutical Preparations Pharmacogenomics 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 Vulnerable Populations antagonist behavioral pharmacology behavioral phenotyping big-data science cancer therapy cell type drug abstinence fentanyl abuse fentanyl seeking fentanyl self-administration fentanyl use gene product genomic biomarker genomic profiles genomic signature imaging approach individual variation interdisciplinary approach medication-assisted treatment 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 pharmacologic 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.

项目概要/摘要阿片类药物的滥用给美国和全世界带来了巨大的公共和经济负担。现有的治疗阿片类药物使用障碍 (OUD) 的药理学方法与针对个体触发因素的行为疗法，以减少或消除过度药物消耗。尽管阿片类药物使用的个体差异已在动物行为模型中反复得到承认，与这种变异性背后的神经生物学适应相关的基因组标记尚不清楚。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，这可能复制个性化癌症治疗的临床成功。根据这个论点，我们假设芬太尼使用升级的个体行为差异与系统水平的差异相关伏隔核和前额皮质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，可以在经过自我给药训练的动物中进行建模在扩大使用条件下的阿片类药物。根据已发表的文献和初步数据，我们建议三个互补的目标是监测行为、功能方面逐步增加的摄入量的发展细胞/网络和基因组水平的分析。我们的目标 1 假设芬太尼摄入量增加出现在对非药物（蔗糖）奖励的敏感性存在个体差异的背景下。寻找支持这一目标的证据有可能在开始使用阿片类药物之前识别弱势个体。目标 2 检查与芬太尼摄入量增加相关的神经元结果。具体来说，我们将评估逐渐增加的摄入量的个体特征是否反映了四种钾对细胞兴奋性调节的改变通道家族以及对单细胞和网络水平神经元输出的影响。作为一部分收集的数据这一目标将确定易受摄入量增加影响的功能性神经元驱动因素。最后，目标3 比较实验动物（大鼠）与人类中芬太尼增量变化的基因组景观阿片类药物使用数据库。为此，我们利用细胞类型特异性 RNA 测序来评估伏隔核和前额皮质摄入量增加的神经元和非神经元机制。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我们的临床前研究结果与人类样本的转化相关性。描述交互的特征行为、功能和基因组水平的分析，开发了一个统一的统计框架线性混合模型来检查行为升级之间双向关系的强度摄入量和分子结果。