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: 10554441
• 负责人: Roxann Roberson-Nay
• 金额: $ 15.53万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554441
• 关键词: Active Biological Transport; Address; Adolescence; Adolescent; Adolescent and Young Adult; Age; Age of Onset; Alleles; Antibodies; Basic Science; Binding; Biological; Biological Process; Bipolar Disorder; Blood; Brain; Cardiovascular Diseases; Cell Lineage; Cell surface; Cells; Central Nervous System; Cerebrospinal Fluid; Characteristics; Child Rearing; Cognition Disorders; DNA Sequence; DSM-V; Data; Databases; Development; Disease; Disease remission; Dizygotic Twins; Elderly; Environmental Risk Factor; Epigenetic Process; Event; Female; Functional disorder; Future; Gene Targeting; General Population; Genes; Genetic; Genomics; Health; Homeostasis; Impairment; Incidence; Individual; Individual Differences; 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; Neurons; Nucleic Acids; Ontology; Parents; Participant; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Physiology; Plasma; Population; Psychopathology; Public Health; Recommendation; 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; analysis pipeline; bioinformatics tool; biological sex; blood-brain barrier crossing; brain cell; brain tissue; burden of illness; candidate identification; cell type; circulating microRNA; depressive symptoms; differential expression; early onset; exRNA Atlas; exosome; extracellular vesicles; genome-wide; genomic locus; improved; indexing; inter-individual variation; lifetime risk; male; mortality; neural; next generation sequencing; peripheral blood; psychiatric genomics; 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.

项目总结