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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要重度抑郁症（MD）非常普遍，在全球疾病负担中排名第二，总体而言一般人群的终生风险估计为 16.2%。1 MD 还与死亡率增加相关，特别是自杀。2 在青少年中，MD 与所有损伤程度最高。精神疾病，16% 的女性和 12% 的男性赞同至少出现过一次重度抑郁症 (MDE) 183 岁；发病年龄过早会增加未来损伤的风险。4 鉴于集体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研究的有希望的候选者。表观遗传机制是生物过程在不改变 DNA 序列的情况下影响基因组健康和调控。小非编码 RNA 是最多样化、数量最多且动态的一类表观遗传机制。他们执行大量调节和功能作用，包括细胞间信号传导。对于精神病学研究，microRNA (miRNA) 是识别与 MD 和风险相关的生物途径的绝佳候选者。5-9 个体间 miRNA谱的差异与病理生理学、药物治疗中的性别差异有关双相情感障碍的反应、10,11 MD 病例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 可以在外周细胞的细胞外囊泡 (ECV) 中获取。血浆。 ECV 轻松穿过血脑屏障 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 可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 病理生理学很重要的生物过程。我们建议利用现有样本确定 ECV miRNA 谱，以研究一段时间内年轻人样本中的 MD 病理生理学 MD 发病率峰值 12-15。具体来说，该提案将以青少年和年轻成人双胞胎研究为基础（NTotal=860 双胞胎；R01MH101518）以提高我们对 miRNA 货物的理解，特别是那些源自神经元，增加了目前对早发性MD病理生理学的理解。父母中的双胞胎 R01 完成了一系列广泛的措施，评估精神病史、与 MD 相关的危险因素、生命压力和逆境、环境因素（例如养育子女）、实验室挑战（例如特里尔社会压力）测试），他们提供了分离血浆的血液。本次R21提案将选择284等离子从父母的同卵双胞胎和异卵双胞胎子集（15-22 岁；~65% 女性）中采集样本 R01 旨在解决有关年轻人中循环 miRNA 的性质及其影响的关键基础科学问题与早年出现的 MD 的关系。这项研究中产生的数据将为科学提供信息青少年/年轻人的发育以及MD的病理生理学。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transcriptome Profiling of Cardiac Glycoside Treatment Reveals EGR1 and Downstream Proteins of MAPK/ERK Signaling Pathway in Human Breast Cancer Cells.

强心苷治疗的转录组分析揭示了人乳腺癌细胞中 EGR1 和 MAPK/ERK 信号通路的下游蛋白。

DOI：
发表时间：
2023-11-02
期刊：
影响因子：
5.6
作者：
Pavithran, Honey;Kumavath, Ranjith;Ghosh, Preetam
通讯作者：
Ghosh, Preetam

COFFEE: Consensus Single Cell-Type Specific Inference for Gene Regulatory Networks.

COFFEE：基因调控网络的共识单细胞类型特异性推断。

DOI：
发表时间：
2024-01-08
期刊：
影响因子：
0
作者：
Lodi, Musaddiq K;Chernikov, Anna;Ghosh, Preetam
通讯作者：
Ghosh, Preetam

Examining indicators of complex network vulnerability across diverse attack scenarios.

检查不同攻击场景中复杂网络漏洞的指标。

DOI：
发表时间：
2023-10-24
期刊：
影响因子：
4.6
作者：
Al Musawi, Ahmad F;Roy, Satyaki;Ghosh, Preetam
通讯作者：
Ghosh, Preetam

CHAI: Consensus Clustering Through Similarity Matrix Integration for Cell-Type Identification.

CHAI：通过相似矩阵积分进行共识聚类以进行细胞类型识别。

DOI：
发表时间：
2024-03-22
期刊：
影响因子：
0
作者：
Lodi, Musaddiq K;Lodi, Muzammil;Osei, Kezie;Ranganathan, Vaishnavi;Hwang, Priscilla;Ghosh, Preetam
通讯作者：
Ghosh, Preetam