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

健康年轻人体内富含 L1CAM 的外泌体 MicroRNA 货物的定量和表征

• 批准号: 10353466
• 负责人: Roxann Roberson-Nay
• 金额: $ 27.17万
• 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: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353466
• 关键词: Active Biological Transport; Address; Adolescence; Adolescent; Adolescent and Young Adult; Age; Age of Onset; Alleles; Antibodies; Basic Science; Biological; Biological Process; Bipolar Disorder; Blood; Brain; Cardiovascular Diseases; Cell Lineage; Cell surface; Cells; Cerebrospinal Fluid; Characteristics; Child Rearing; Cognition Disorders; DNA Sequence; DSM-V; Data; Databases; Development; Disease; Dizygotic Twins; Elderly; Ensure; Environmental Risk Factor; Epigenetic Process; Event; Female; Functional disorder; Future; Gene Targeting; General Population; Genes; Genetic; Genomics; Gold; Health; Homeostasis; Impairment; Individual; Intervention; Laboratories; Life; Life Stress; Link; Long-Term Effects; Major Depressive Disorder; Malignant Neoplasms; Maps; Measures; Membrane; Mental Depression; Mental disorders; Methods; MicroRNAs; Modeling; Monozygotic twins; NCAM1 gene; Nature; Neural Cell Adhesion Molecule L1; Neuraxis; Neurons; Nucleic Acids; Ontology; Parents; Participant; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Physiology; Plasma; Population; Psychopathology; Public Health; Recording of previous events; Recurrence; Regulation; Research; Ribosomal RNA; Risk; Risk Estimate; Risk Factors; Role; Sampling; Science; Severities; Signal Transduction; Suicide; Technology; Testing; Tissues; Transcript; Transcriptional Regulation; Traumatic Brain Injury; Trier Social Stress Test; Twin Multiple Birth; Twin Studies; Untranslated RNA; Vesicle; base; bioinformatics tool; biological sex; brain cell; brain tissue; burden of illness; cell type; circulating microRNA; depressive symptoms; differential expression; early onset; exRNA Atlas; extracellular vesicles; genome-wide; genomic locus; improved; indexing; inter-individual variation; lifetime risk; male; mortality; next generation sequencing; peripheral blood; psychiatric genomics; relating to nervous system; response; sex; single episode major depressive disorder; transcriptome sequencing; vesicular release; young adult

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.

项目摘要 严重抑郁症（MD）高度普遍，在全球疾病负担中排名第二，总体上排名 终生风险估计为普通人群16.2％。1MD还与死亡率增加有关， 2在青少年中，医学博士与所有人最大程度的损害相关联 精神病病，有16％的女性和12％的男性认可至少一个主要的抑郁发作 （MDE）到183岁；发病年龄的年龄增加了未来损害的风险。4鉴于集体 遗传因素和环境事件对MD风险责任和进展，表观遗传的影响 机制是MD研究的有希望的候选人。表观遗传机制是生物学过程 影响基因组健康和调节而不改变DNA序列。小型非编码RNA是 最多样化，众多和动态的表观遗传机制。他们执行大量 调节和功能作用，包括细胞间信号。对于精神病研究，microRNA（miRNA） 是识别与MD和风险相关的生物学途径的绝佳候选者。5-9个个体 miRNA谱的差异与病理生理学，药物的基于性别的差异有关 双相情感障碍的反应，10,11个当前的抑郁症状严重程度在MD病例中和MD病例状态。 重要的是，可以在外周的细胞外囊泡（ECV）中访问来自脑细胞谱系的miRNA 血浆。 ECV很容易穿越血脑屏障9和神经衍生的差异货物分析 外周血的ECV是可能的。12安装证据强调了外周血的潜力 ECV绘制中枢神经系统细胞类型的疾病轨迹，并提供大脑快照 可能对MD病理生理学显着的生物学过程。我们建议利用现有样品 确定ECV miRNA轮廓以研究年轻人样本中MD病理生理学 峰值MD发病率12-15。具体而言，该建议将基于青少年和年轻的成人双胞胎研究 （ntotal = 860个双胞胎； R01MH101518），以提高我们对miRNA货物的理解，尤其是从 神经元，以增加对早期MD病理生理学的当前理解。父母双胞胎 R01完成了一系列评估精神病病史，与MD相关的风险因素的措施 压力和逆境，环境因素（例如，育儿），实验室挑战（例如Trier社会压力 测试），它们提供了血浆分离的血液。该R21提案将选择284个等离子体 从父母的单卵双胞胎和双卵双胞胎（年龄〜65％的女性）子集收集的样品 R01解决了有关年轻人及其循环miRNA及其的性质的关键基础科学问题 与MD的关系，生命早期就开始了。本研究中产生的数据将为科学提供信息 青少年/年轻成人发展以及MD的病理生理学。