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

项目摘要 酒精是青少年和年轻人中最常用和滥用的物质。醇 在生命早期的消费可以产生持久的神经生物学后果，因为青春期/年轻 成年期是一个关键时期，其特征是大脑显著和持续的成熟。调查 神经病理生理学突出的酒精使用（Au）是具有挑战性的，因为来自活人的脑组织不容易 可进行纵向测量。我们建议通过调查以下方面的作用来规避这一挑战： 年轻人Au神经生物学中的细胞外囊泡货物。ECV是膜结合囊， 生物活性物质遍布全身。8它们作为生理学的正常部分由所有组织释放， 包括脑神经元，并且血浆ECV特征的偏差与精神病相关， 物质使用和认知障碍。特别是，比较ECV货物分析是有意义的，因为ECV 货物反映了组织的起源，并可用于推断ECV在靶细胞，病理生理学， 治疗反应。微小RNA（miRNAs）构成血浆ECV货物的大部分36，使其成为血浆ECV货物的主要组成部分。 基础科学ECV研究的最佳初始目标。miRNAs是理解基因组的有吸引力的候选者。 在动物和人类研究中，它们自身具有Au的结构，并与Au相关。重要的是， 从脑细胞谱系可以在外周血血浆中获得，提供了一个机会，索引脑生物学 这些过程可能对Au神经生物学很重要。我们建议利用现有的生物标本来测量ECV- 在高Au时期，研究青少年和年轻成年人样本中的Au病理生理学。 具体而言，该提案将利用从现有队列收集的数据（父母R 01 MH 101518; Ntotal=860对双胞胎; 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， 以增加目前对早期生命Au的神经生物学的理解。我们将选择N=313名参与者（年龄15-22岁; 52%的女性），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、生活压力源/逆境）。 母体R 01的受试者还提供了分离血浆的血液。这份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， 生活中

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.