Characterizing the Relationship Between Alcohol Consumption and Neuron-Derived Exosomal MicroRNA Cargo in an Adolescent-Young Adult Twin Cohort

青少年双胞胎队列中酒精消耗与神经元衍生的外泌体 MicroRNA 货物之间关系的表征

• 批准号: 10613564
• 负责人: Roxann Roberson-Nay
• 金额: $ 14.55万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613564
• 关键词: Active Biological Transport; Address; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Age; Alcohol consumption; Alcohols; Animal Model; Animals; Basic Science; Binding; Biological; Biological Assay; Biological Process; Blood; Body mass index; Brain; Cannabis; Cell Lineage; Cell surface; Cells; Characteristics; Child Rearing; Clinical; Cognition Disorders; Complement; Consumption; DSM-V; Data; Databases; Disease; Electronics; Environmental Exposure; Evaluation; Female; Frequencies; Functional disorder; Genes; Heavy Drinking; Homeostasis; Hour; Human; Individual; Intervention; Interview; Life; Link; Long-Term Effects; Longitudinal cohort; Measurement; Measures; Membrane; Mental disorders; Methods; MicroRNAs; Modeling; Nature; Network-based; Neural Cell Adhesion Molecule L1; Neurobiology; Neurons; Nucleic Acids; Ontology; Parents; Participant; Pathway interactions; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Physiology; Plasma; Population; Public Health; RNA; Recording of previous events; Regulation; Research; Risk; Role; Sampling; Signal Transduction; Symptoms; Technology; Testing; Thick; Tissues; Transcript; Transcriptional Regulation; Twin Multiple Birth; Vesicle; alcohol exposure; alcohol misuse; alcohol use disorder; alcohol use initiation; binge drinking; bioinformatics tool; biological sex; biomarker identification; blood-brain barrier crossing; brain cell; brain tissue; chronic alcohol ingestion; circulating microRNA; cohort; combustible cigarette; comparative; computerized; critical period; differential expression; early alcohol use; electronic cigarette use; exosome; extracellular vesicles; genetic architecture; gray matter; improved; indexing; innovation; interest; male; next generation sequencing; peripheral blood; problem drinker; psychiatric symptom; sex; stressor; substance misuse; substance use; vesicular release; young adult

Project Summary Alcohol is the most commonly used and misused substance amongst adolescents and young adults. Alcohol consumption during early life can produce persistent neurobiological consequences given that adolescence/young adulthood is a critical period characterized by significant and ongoing brain maturation. Investigating the neuropathophysiology salient to alcohol use (AU) is challenging given that brain tissue from living humans is not readily accessible for longitudinal measurement. We propose to circumnavigate this challenge by investigating the role of extracellular vesicle cargo in AU neurobiology of young people. ECVs are membrane-bound sacs that transport biologically active materials throughout the body.8 They are released by all tissues as a normal part of physiology, including brain neurons, and deviations in blood plasma ECV characteristics have been associated with psychiatric, substance use, and cognitive disorders. In particular, comparative ECV cargo analyses are of interest because ECV cargo reflects tissue of origin and may be used to infer functional roles for ECVs in target cells, pathophysiology, and treatment responsiveness. MicroRNAs (miRNAs) comprise a majority of blood plasma ECV cargo36, making them the best initial target for basic science ECV research. MiRNAs are attractive candidates for understanding the genetic architecture of AU in their own right and have been associated with AU in animal and human studies. Importantly, ECVs from brain cell lineages can be accessed in peripheral blood plasma, providing an opportunity to index brain biological processes that may be salient to AU neurobiology. We propose to leverage existing biospecimens to measure ECV- miRNAs and investigate AU pathophysiology in a sample of adolescents and young adults during a period of high AU. Specifically, this proposal will leverage data collected from an existing cohort (Parent R01 MH101518; Ntotal=860 twins; ages 15-22; 57% female) to improve our understanding of ECV-miRNA cargo, particularly those deriving from neurons, to add to the current understanding of the neurobiology of early life AU. We will select N=313 participants (ages 15-22; 52% female) from the parent R01, which included a broad and rich assessment of alcohol use, concurrent substance use, psychiatric history and symptoms, and environmental exposures (e.g., parenting, life stressors/adversity). Participants in the parent R01 also provided blood from which plasma was separated. This R21 proposal will address critical basic science questions about the nature of circulating miRNAs in young people and their relationship to AU early in life.

项目摘要 酒精是青少年和年轻人中最常使用和滥用的物质。酒精 考虑到青春期/青年时期的消费可能会产生持续的神经生物学后果 成年期是大脑显著成熟和持续成熟的关键时期。调查 酒精使用(AU)的神经病理生理学是具有挑战性的，因为活人的脑组织并不容易 可用于纵向测量。我们建议通过调查以下角色来绕过这一挑战 年轻人的AU神经生物学中的胞外囊泡。ECV是结合在膜上的囊，可以运输 生物活性物质遍布全身。作为生理的正常部分，它们由所有组织释放， 包括脑神经元，以及血浆ECV特征的偏差与精神疾病有关， 物质使用和认知障碍。特别是，ECV货物的比较分析是有意义的，因为ECV Cargo反映了起源的组织，并可用于推断ECV在靶细胞、病理生理学和 治疗反应性。MicroRNAs(MiRNAs)构成血浆ECV组分的大部分36，使它们成为 基础科学ECV研究的最佳初始目标。MiRNAs是理解基因的有吸引力的候选者 它们本身就是非盟的建筑，并在动物和人类研究中与非盟联系在一起。重要的是，ECV 来自脑细胞的谱系可以在外周血浆中获得，这为索引大脑生物学提供了机会 这些过程可能是AU神经生物学的显著特征。我们建议利用现有的生物标本来测量ECV- MiRNAs，并在高AU时期对青少年和年轻人样本进行AU病理生理学研究。 具体地说，这项建议将利用从现有队列(父母R01 MH101518；NTotal=860双胞胎； 年龄15-22岁；57%女性)，以提高我们对ECV-miRNA货物的理解，特别是那些来自神经元的货物， 以增加目前对AU早期神经生物学的理解。我们将选出N=313名参与者(年龄15-22岁； 52%的女性)来自亲本R01，其中包括对酒精使用的广泛和丰富的评估，同时存在物质 使用、精神病史和症状，以及环境暴露(例如，育儿、生活压力源/逆境)。 亲本R01的参与者也提供了血浆分离的血液。此R21提案将解决 关于年轻人循环中miRNAs的性质及其与AU早期关系的关键基础科学问题 在生活中。