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

• 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
• 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

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.

项目摘要 酒精使用障碍和疼痛是影响美国数百万人的主要公共健康问题 各州。2019年，超过1400万美国人符合澳元病的诊断标准，2019年有5000万人符合澳元病的诊断标准 据估计，美国人患有慢性疼痛。这些公共卫生危机是相互关联的，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 罹患澳门氏症的风险较高。饮酒止痛是一种不适应的策略， 可能会导致戒断引起的痛觉过敏、周围神经病变和AUD。虽然酒精会给你带来 止痛作用呈剂量依赖关系，基因差异意味着不是每个人都经历过 这种止痛的程度是一样的。以前的研究已经显示出中到强的遗传力(h2=0.42) 乙醇对C57BL/6J和DBA/2J小鼠的镇痛作用，但这种关系背后的基因仍然 特征不佳的。对啮齿动物模型的研究表明，阿片受体系统，GIRK2 钾通道和GABA能信号通路都在乙醇镇痛中起作用，但不是全部参与。 已经进行了基因组审讯。该项目旨在识别调节酒精的候选基因-- 用互补的遗传、行为和转录实验对小鼠的镇痛作用 信息量丰富的BXD小鼠种群。通过定位基础和酒精后的数量性状基因座(QTL) 热板潜伏期与BXD菌株，我们将确定与乙醇诱导的变异连锁的基因组座位 止痛药。作为另一种全基因组方法，前额叶皮质和中脑导水管周围的灰色样本来自 对高、低乙醇镇痛BXD菌株进行RNA-seq研究。我们将进行加权基因联合 表达网络分析(WGCNA)筛选这两种镇痛中的差异表达基因 组。通过结合来自行为、统计和分子方法的证据，我们将选择 高表达或高表达用于实验验证的最强乙醇镇痛候选基因 基因敲除的老鼠模型。这项提案包括从确定候选人开始的调查过程 通过QTL定位基因，阐明大脑关键区域的基因表达模式，验证酒精 止痛候选基因。这对应聘者来说是一个很好的培训机会，可以设计和 进行一系列系统遗传学和动物行为实验，并为科学研究做出贡献 对物质诱导镇痛的理解。