Elucidating causal mechanisms of ethanol-induced analgesia in BXD recombinant inbred mouse lines

阐明 BXD 重组近交系小鼠乙醇诱导镇痛的因果机制

基本信息

批准号：
10825737
负责人：
Walker David Rogers
金额：
$ 4.21万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-10 至 2026-09-09
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10825737
关键词：
Absence of pain sensation Acute Address Affect Alcohol consumption Alcohols Algorithms American Analgesics Animals Behavioral Behavioral Genetics Bioinformatics Biological Biological Assay Brain region Candidate Disease Gene Characteristics Data Databases Development Dose Ensure Environmental Risk Factor Ethanol Event GIRK2 subunit, G protein-coupled inwardly-rectifying potassium channel Gene Expression Gene Expression Profile Gene Expression Profiling Gene Modified Gene Targeting Genes Genetic Genetic study Genotype Heritability Human Hyperalgesia Inbred Mouse Informatics Knockout Mice Link Literature Maps Mediation Methodology Molecular Mus Nociception Opioid Receptor Pain Pain management Pathway Analysis Pathway interactions Pattern Peripheral Nervous System Diseases Persons Phenotype Population Potassium Channel Prefrontal Cortex Process Property Public Health Quantitative Trait Loci Reaction Time Recombinants Reporting Research Risk Rodent Model Role Sampling Signal Pathway Source Symptoms System Tissue-Specific Gene Expression Training United States Variant Viral Vector Withdrawal addiction alcohol use disorder antinociception attenuation behavioral phenotyping behavioral response bioinformatics resource candidate identification candidate validation chronic alcohol ingestion chronic pain chronic painful condition design diagnostic criteria differential expression experience experimental study gene network genetic architecture genome wide association study genome-wide genomic locus large-scale database mechanical allodynia midbrain central gray substance model organism mouse genome mouse model neural circuit overexpression pain symptom phenomics response training opportunity trait transcriptome sequencing transcriptomics trend whole genome

项目摘要

Project Summary Alcohol use disorder (AUD) and pain are major public health problems affecting millions of people in the United States. More than 14 million Americans met the diagnostic criteria for AUD in 2019, and 50 million people in the United States were estimated to have a chronic pain condition. These public health crises are related, as people experiencing pain often report using alcohol to manage pain symptoms, and people with chronic pain are at an elevated risk for developing AUD. Drinking alcohol to alleviate pain is a maladaptive strategy and may lead to withdrawal-induced hyperalgesia, peripheral neuropathy, and AUD. While alcohol confers analgesic effects in a dose-dependent manner, genetic differences mean that not every person experiences this analgesia to the same degree. Previous research has revealed moderate-to-strong heritability (h2=0.42) for ethanol-induced analgesia in C57BL/6J and DBA/2J mice, but the genes underlying this relationship are still poorly characterized. Studies in rodent models have revealed evidence that opioid receptor systems, GIRK2 potassium channels, and GABAergic signaling pathways all have roles in ethanol analgesia, but no whole- genome interrogations have been conducted. This project aims to identify candidate genes modulating alcohol- induced analgesia using complementary genetic, behavioral and transcriptomic experiments in genetically informative BXD mouse populations. By mapping quantitative trait loci (QTL) for both basal and post-ethanol hot plate latency with BXD strains, we will identify genomic loci linked with variation in ethanol-induced analgesia. As an additional genome-wide approach, prefrontal cortex and periaqueductal gray samples from high- and low-ethanol analgesia BXD strains will be studied by RNA-seq. We will perform weighted gene co- expression network analysis (WGCNA) to identify differentially expressed genes in these two analgesia groups. By combining evidence from behavioral, statistical, and molecular methodologies, we will select the strongest ethanol analgesia candidate gene for experimental verification using either overexpression or knockout mouse models. This proposal comprises an investigative progression from identifying candidate genes by QTL mapping, to elucidating gene expression patterns in critical brain regions, to validating ethanol analgesia candidate genes. It represents an outstanding training opportunity for the candidate to design and perform a suite of systems genetics and animal behavioral experiments and contribute to the scientific understanding of substance-induced analgesia.

项目概要酒精使用障碍 (AUD) 和疼痛是影响数百万人的美国主要公共卫生问题国家。 2019 年，超过 1400 万美国人符合 AUD 诊断标准，其中 5000 万人符合 AUD 诊断标准。据估计，美国患有慢性疼痛。这些公共卫生危机是相关的，因为经历疼痛的人经常报告使用酒精来控制疼痛症状，而患有慢性疼痛的人患澳元的风险较高。饮酒来缓解疼痛是一种适应不良的策略，并且可能导致戒断引起的痛觉过敏、周围神经病变和 AUD。虽然酒精赋予镇痛效果呈剂量依赖性，遗传差异意味着并非每个人都会经历这种镇痛程度相同。先前的研究表明，中等到强的遗传力（h2 = 0.42） C57BL/6J 和 DBA/2J 小鼠中乙醇诱导的镇痛作用，但这种关系背后的基因仍然存在特征不佳。对啮齿动物模型的研究揭示了阿片受体系统 GIRK2 的证据钾通道和 GABA 信号通路均在乙醇镇痛中发挥作用，但没有完整的已经进行了基因组询问。该项目旨在确定调节酒精的候选基因使用互补的遗传、行为和转录组实验在遗传上诱导镇痛信息丰富的 BXD 小鼠群体。通过绘制基础和乙醇后的数量性状基因座 (QTL) BXD 菌株的热板潜伏期，我们将鉴定与乙醇诱导的变异相关的基因组位点镇痛。作为另一种全基因组方法，前额皮质和导水管周围灰色样本来自高乙醇和低乙醇镇痛 BXD 菌株将通过 RNA 测序进行研究。我们将进行加权基因协同表达网络分析（WGCNA）来识别这两种镇痛中的差异表达基因组。通过结合行为、统计和分子方法学的证据，我们将选择最强的乙醇镇痛候选基因，用于使用过表达或基因敲除小鼠模型。该提案包括从确定候选人开始的调查进展通过 QTL 作图分析基因，阐明关键大脑区域的基因表达模式，验证乙醇镇痛候选基因。它为候选人设计和设计提供了绝佳的培训机会进行一系列系统遗传学和动物行为实验，并为科学做出贡献了解物质诱导镇痛。