2/11 Spatially Resolved, Single Cell, Neuroimmune Transcriptomes in Alcohol Dependence

2/11 酒精依赖中的空间分辨、单细胞、神经免疫转录组

基本信息

批准号：
10412407
负责人：
R. DAYNE MAYFIELD
金额：
$ 57.52万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-05 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10412407
关键词：
Agonist Alcohol consumption Alcohol dependence Alcohols Anatomy Animal Model Animals Autopsy Biological Assay Brain Candidate Disease Gene Cell Nucleus Cells Characteristics Chronic Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Data Data Set Development Feedback Gene Expression Genes Genetic Heavy Drinking Human Human Genome Immune Immune signaling Individual Inflammatory Innate Immune System Link Maps Mediating Molecular Multiomic Data Mus Mutation Neuroglia Neuroimmune Pathway interactions Phenotype Play Prefrontal Cortex Reporter Resolution Rodent Model Role Signal Transduction Small Nuclear RNA TLR7 gene Techniques Technology Validation Variant Viral Vector Work alcohol exposure alcohol use disorder behavioral phenotyping brain cell cell type data integration drinking drinking behavior gene network genome wide association study genomic locus human model improved in vivo evaluation member mouse model multiple omics preference problem drinker response therapeutic target tool transcriptome transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract Neuroimmune signaling is strongly implicated in the development and progression of alcohol use disorder (AUD). Innate immune molecules are upregulated in human postmortem brains from alcoholics and are correlated with lifetime alcohol use. Human genome-wide association studies (GWAS) also link immune/inflammatory genes to alcohol dependence. We hypothesize that alcohol consumption initiates a positive feedback loop involving neuroimmune activation and proinflammatory responses that promote excessive alcohol consumption. Neuroimmune signaling also regulates voluntary alcohol consumption in rodent models and activation of specific pathways results in escalation of drinking. Our recent work shows that immune signaling in glial cells have emerged as key regulators of alcohol drinking. Using single cell and spatial transcriptome technologies, we are now able to precisely define the role of individual types of brain cells in the context of excessive alcohol consumption. Our overarching hypothesis is phenotypic changes characteristic of escalated alcohol consumption and preference are due, in part, to spatially distinct and cell-specific molecular mechanisms that significantly reshape the neuroimmune transcriptome. Multi-omic genetic changes at the cellular level from human and animal models will reveal new gene candidates and therapeutic targets.

项目摘要/摘要神经免疫信号与酒精使用的发展和发展密切相关障碍（AUD）。酗酒者和与终身饮酒有关。人类全基因组协会研究（GWAS）也联系免疫/炎症基因对酒精依赖性。我们假设饮酒会启动涉及神经免疫性激活和促炎反应的积极反馈回路促进过度饮酒。神经免疫性信号传导还调节自愿饮酒啮齿动物模型和特定途径的激活导致饮酒的升级。我们最近的工作表明神经胶质细胞中的免疫信号传导已成为饮酒的关键调节剂。使用单细胞和空间转录组技术，我们现在能够精确地定义单个类型的脑细胞在过度饮酒的背景。我们的总体假设是表型变化的特征升级的酒精消耗和偏好部分归因于空间上不同的细胞特异性分子显着重塑神经免疫转录组的机制。多运动遗传变化人类和动物模型的细胞水平将揭示新的基因候选物和治疗靶标。