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: 10452928
• 负责人: Roxann Roberson-Nay
• 金额: $ 26.2万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452928
• 关键词: Active Biological Transport; Address; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Age; Alcohol consumption; Alcohols; Animal Model; Animals; Basic Science; Biological; Biological Assay; Biological Markers; Biological Process; Blood; Blood - brain barrier anatomy; Body mass index; Brain; Cannabis; Cell Lineage; Cell surface; Cells; Characteristics; Child Rearing; Clinical; Cognition Disorders; Complement; Consumption; DSM-V; Data; Databases; Disease; Environmental Exposure; Evaluation; Female; Frequencies; Functional disorder; Genes; Gold; 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; Tissues; Transcript; Transcriptional Regulation; Twin Multiple Birth; Vesicle; alcohol exposure; alcohol misuse; alcohol use disorder; alcohol use initiation; base; binge drinking; bioinformatics tool; biological sex; brain cell; brain tissue; chronic alcohol ingestion; circulating microRNA; cohort; combustible cigarette; comparative; computerized; critical period; differential expression; early alcohol use; electronic cigarette use; 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.

项目概要 酒精是青少年和年轻人中最常用和滥用的物质。酒精 鉴于青春期/年轻人，生命早期的消费可能会产生持续的神经生物学后果 成年期是一个关键时期，其特点是大脑持续显着成熟。调查 鉴于活体人类的脑组织不容易被研究，因此与酒精使用（AU）相关的神经病理生理学具有挑战性。 可进行纵向测量。我们建议通过调查以下角色来规避这一挑战： 年轻人所有神经生物学中的细胞外囊泡货物。 ECV 是膜结合囊，负责运输 遍布全身的生物活性物质。8 它们作为生理的正常部分由所有组织释放， 包括脑神经元，血浆 ECV 特征的偏差与精神、 物质使用和认知障碍。特别是，比较 ECV 货物分析很有趣，因为 ECV 货物反映了起源组织，可用于推断 ECV 在靶细胞中的功能作用、病理生理学和 治疗反应性。 MicroRNA (miRNA) 构成了血浆 ECV 货物的大部分36，这使得它们成为 基础科学 ECV 研究的最佳初始目标。 miRNA 是理解遗传基因的有吸引力的候选者 AU 的建筑本身具有独立性，并且在动物和人类研究中与 AU 相关。重要的是，ECV 可以在外周血浆中获取来自脑细胞谱系的信息，从而为索引脑生物提供了机会 对所有神经生物学来说可能很重要的过程。我们建议利用现有的生物样本来测量 ECV- miRNA 并研究高 AU 时期青少年和年轻人样本中的 AU 病理生理学。 具体来说，该提案将利用从现有队列（父母 R01 MH101518；Ntotal=860 双胞胎； 15-22岁； 57% 女性）以提高我们对 ECV-miRNA 货物的理解，特别是那些源自神经元的货物， 补充当前对早期生命 AU 神经生物学的理解。我们将选择 N=313 名参与者（15-22 岁； 52% 女性）来自母体 R01，其中包括对酒精使用、并发物质的广泛而丰富的评估 使用、精神病史和症状以及环境暴露（例如养育子女、生活压力/逆境）。 父母 R01 的参与者还提供了分离血浆的血液。该 R21 提案将解决 关于年轻人中循环 miRNA 的性质及其与早期 AU 的关系的关键基础科学问题 在生活中。