Quantification and Characterization of Bulk and L1CAM-Enriched Exosomal MicroRNA Cargo in Healthy Young People

项目摘要 重性抑郁症（MD）非常普遍，在全球疾病负担中排名第二， 在一般人群中估计终生风险为16.2%。MD还与死亡率增加相关， 2在青少年中，MD与所有障碍的最大程度相关 精神疾病，16%的女性和12%的男性至少有一次重度抑郁发作 (MDE)到183岁;早期发病会增加未来损伤的风险。 遗传因素和环境事件对MD风险倾向和进展的影响，表观遗传 机制是MD研究的有前途的候选者。表观遗传机制是生物学过程， 在不改变DNA序列的情况下影响基因组健康和调控。小的非编码RNA是 最多样化的，众多的，和动态的一类表观遗传机制。他们执行大量的 调节和功能作用，包括细胞间信号传导。对于精神病学研究，microRNAs（miRNAs） 是识别与MD和风险相关的生物学途径的极好候选者。5 -9个体间 miRNA谱的差异与病理生理学、药物治疗、 双相情感障碍的反应，10，11 MD病例中当前抑郁症状的严重程度，以及MD病例状态。 重要的是，来自脑细胞谱系的miRNA可以在外周血中的细胞外囊泡（ECV）中被获取。 血浆ECV很容易穿过血脑屏障9和神经源性的差异货物分析 来自外周血的ECV是可能的。12越来越多的证据强调了外周血的潜力。 ECV用于绘制中枢神经系统细胞类型的疾病轨迹并提供大脑的快照 可能对MD病理生理学显著的生物过程。我们建议利用现有的样本 确定ECV miRNA谱，以研究一段时间内年轻人样本中的MD病理生理学 峰值MD入射率12 -15。具体而言，这项建议将建立在青少年和年轻成人双胞胎研究的基础上。 （NTotal=860对双胞胎; R 01 MH 101518），以提高我们对miRNA货物的理解，特别是那些来自 神经元，以增加目前对早发性MD的病理生理学的理解。父母双胞胎 R 01完成了一系列广泛的测量，评估精神病史、与MD相关的风险因素、生活质量、 压力和逆境，环境因素（例如，养育），实验室挑战（例如，特里尔社会应激 试验），他们提供了血浆分离的血液。本R21提案将选择284等离子体 从父母的单卵双胞胎和双卵双胞胎（年龄15-22岁;约65%为女性）中采集样本 R 01旨在解决关于年轻人循环miRNAs的性质及其 与早期发病的MD的关系。本研究产生的数据将为科学提供信息， 青少年/年轻成人发育以及MD的病理生理学。

Project Summary Major depression (MD) is highly prevalent, ranking second in the global burden of disease, with the overall lifetime risk estimated to be 16.2% in the general population.1 MD also is associated with increased mortality, particularly suicide.2 Amongst adolescents, MD is associated with the greatest level of impairment of all psychiatric conditions, with 16% of females and 12% of males endorsing at least one major depressive episode (MDE) by age 183; an early age of onset confers increased risk for future impairment.4 Given the collective influence of genetic factors and environmental events on MD risk liability and progression, epigenetic mechanisms are promising candidates for MD research. Epigenetic mechanisms are biological processes that influence genomic health and regulation without changing the DNA sequence. Small noncoding RNAs are the most diverse, numerous, and dynamic class of epigenetic mechanisms. They perform a large number of regulatory and functional roles, including intercellular signaling. For psychiatric research, microRNAs (miRNAs) are an excellent candidate for identifying biological pathways associated with MD and risk.5-9 Interindividual differences in miRNA profiles have been associated with sex-based differences in pathophysiology, medication response in bipolar disorder,10,11 current depressive symptom severity in MD cases, and MD case status. Importantly, miRNAs from brain cell lineages can be accessed in extracellular vesicles (ECVs) in peripheral blood plasma. ECVs easily cross the blood brain barrier9 and differential cargo analysis of neurally-derived ECVs from peripheral blood is possible.12 Mounting evidence underscores the potential for peripheral blood ECVs to map disease trajectories of central nervous system cell type and to provide a snapshot of brain biological processes that may be salient to MD pathophysiology. We propose to leverage existing samples to determine ECV miRNA profiles to investigate MD pathophysiology in a sample of young people during a period of peak MD incidence12-15. Specifically, this proposal will build on the Adolescent and Young Adult Twin Study (NTotal=860 twins; R01MH101518) to improve our understanding of miRNA cargo, particularly those deriving from neurons, to add to the current understanding of the pathophysiology of early-onset MD. Twin pairs in the parent R01 completed a broad battery of measures assessing psychiatric history, risk factors associated with MD, life stress and adversities, environmental factors (e.g., parenting), laboratory challenges (e.g., Trier Social Stress Test), and they provided blood from which plasma was separated. This R21 proposal will select 284 plasma samples collected from a subset of monozygotic and dizygotic twins (ages 15-22; ~65% female) from the parent R01 to address critical basic science questions about the nature of circulating miRNAs in young people and their relationship to MD that onsets early in life. Data generated in this study will inform the science of adolescent/young adult development as well as the pathophysiology of MD.