Human brain multi-omics to decipher major depression pathophysiology

人脑多组学破译重度抑郁症病理生理学

基本信息

批准号：
10715962
负责人：
Maura Boldrini
金额：
$ 79.76万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10715962
关键词：
ATAC-seq Adult Age Amygdaloid structure Anatomy Animal Model Antidepressive Agents Apoptosis Astrocytes Atlases Autopsy Bar Codes Biological Assay Brain Brain Diseases Cell Adhesion Cell Cycle Inhibition Cell Lineage Cell Nucleus Cell Survival Cell model Cell physiology Cells Chromatin Complex Custom Cytoplasmic Granules DNA Repair Data Decision Making Disease Emotional Epigenetic Process Female Functional disorder Gene Expression Regulation Genes Genomics Glucocorticoid Receptor Heterogeneity Hippocampus Human Hydrocortisone Immunity Inflammation Life Link Longevity Major Depressive Disorder Maps Mass Spectrum Analysis Memory Messenger RNA Meta-Analysis Microglia Mitosis Molecular Mus Neurites Neuroglia Neuronal Plasticity Neurons Ontology Pathogenesis Pathogenicity Patients Phenotype Pilot Projects Predisposition Prefrontal Cortex Proliferating Proteins Proteomics Published Database Publishing RNA RNA Splicing Reporting Resolution Rewards Rodent Sampling Severities Slide Stress Sudden Death Technology Testing Tissues Toxicology Transposase Uniport Variant Woman XCL1 gene adult neurogenesis allostatic load biomarker identification cell determination cognitive function dentate gyrus depressive symptoms differential expression early life adversity economic cost emotional functioning epigenomics excitatory neuron genetic variant genome wide association study granule cell high risk hippocampal pyramidal neuron inhibitory neuron mRNA Expression male mood regulation multiple omics neurogenesis neuron loss neuropsychiatry new technology new therapeutic target prevent progenitor response single nucleus RNA-sequencing social stem cell proliferation suicidal risk synaptogenesis transcription factor transcriptomics treatment response

项目摘要

Major depressive disorder (MDD) is a common disease with high risk of suicide, great social and economic costs, and poor treatment response. Hippocampus neuroplasticity is altered in MDD, susceptible to stress exposure and critical for mood regulation and the establishment of emotional memories in MDD. At the cellular level, our group and others reported fewer granule neurons, fewer astrocytes, and smaller dentate gyrus in MDD. There are conflicting findings about the extent to which new neurons are generated in adult humans, and we showed this happens into the eighth decade of life, while other groups were unable to confirm these findings. Adult neurogenesis is linked to both the pathogenesis of depressive phenotypes and the action of antidepressants in mouse studies. Pathogenic mechanisms underlying cellular and anatomical changes in MDD remain largely unknown. A meta-analysis from the three largest genome-wide association studies identified 102 independent variants, 269 genes, and 15 gene-sets associated with MDD. There is an urgent need for using new technologies to investigate cell lineages in human hippocampus. This project will identify differentially expressed proteins (DEPs) and genes (DEGs) between MDD and non- psychiatric control (CTRL) hippocampus, at a regional and single cell level. In homogenized hippocampus tissue, we will implement our proteomics pipeline using high resolution mass spectrometry (HRMS), single nuclei (sn)RNA-seq and snATAC (Assay for Transposase-Accessible Chromatin) sequencing. In slide-mounted tissue we will apply Visium (10X Genomics) and our custom-made slide-seq technology, using deterministic barcoding for spatial omics sequencing, co-mapping mRNAs, ATAC and proteins (DBiT-seq). Our pilot proteomics studies showed that DEPs lower in uMDD vs. CTRL promote mitosis, differentiation, and prevent apoptosis. Pilot snRNA-seq and snATAC-seq identified all types of neurons and glia, vasculature, and immature cell clusters, which mapped with Visium onto the expected hippocampus subfields. DBiT-seq pilot studies showed higher variability of RNA splicing in MDD vs. CTRL, RNA velocity revealed high transcriptomic instability in MDD leading to high inter-patient heterogeneity in the pyramidal neuron cluster, and epigenetic ATAC profiling identified markers potentially related to MDD pathogenesis. Studying 80 MDD and 80 CTRL, age 14-90 yrs., 60% males and 40% females, with sudden death, short agonal state, clear toxicology, postmortem interval<24 hrs., RNA integrity number (RIN)>8, tissue pH>6, we will: 1. Identify hippocampus DEPs between MDD and CTRL applying HRMS. 2. Identify cell clusters’ DEGs in MDD vs. CTRL hippocampus applying snRNA- seq and snATAC-seq. 3. Deliver the first hippocampus spatial transcriptomic atlas and epigenomic atlas for chromatin accessibility, identify region-specific RNA dynamics, and determine MDD vs. CTRL multiome differences applying DBiT-seq. Identified molecular regulators of hippocampus cell viability and function will provide potential druggable targets for new MDD treatments, to be later tested in cellular and animal models.

重度抑郁症（MDD）是一种常见疾病，有自杀，巨大的社会和经济成本的高风险，和治疗反应不佳。在MDD中，海马神经塑性改变了，易受应力暴露对于情绪调节和在MDD中建立情感记忆至关重要。在细胞水平，我们小组等人报告的颗粒神经元，较少的星形胶质细胞和较小的齿状回MDD。那里关于成年人的新神经元产生的程度的矛盾发现，我们表明这发生在生命的第八个十年中，而其他团体则无法确认这些发现。成人神经发生与抑郁表型的发病机理和抗抑郁药在小鼠研究。 MDD的细胞和解剖学变化背后的致病机制仍然在很大程度上未知。来自三大全基因组关联研究的荟萃分析确定了102个独立的与MDD相关的变体，269个基因和15个基因。迫切需要使用新技术研究人海马中的细胞谱系。这项目将确定MDD和非 - 在区域和单细胞水平上，精神病对照（CTRL）海马。在均质的海马组织中我们将使用高分辨率质谱（HRMS），单核实施蛋白质组学管道（SN）RNA-SEQ和SNATAC（转座酶可访问染色质的测定）测序。在幻灯片安装的组织中我们将使用确定性条形码应用，应用visium（10倍基因组学）和我们的定制幻灯片技术技术用于空间幻序列，共映射mRNA，ATAC和蛋白质（DBIT-SEQ）。我们的试点蛋白质组学研究表明，UMDD与CTRL的DEP较低，促进有丝分裂，分化和预防凋亡。飞行员snRNA-seq和snatac-seq鉴定了所有类型的神经元和神经胶质，脉管系统和未成熟的细胞簇，将其映射到预期的海马子场上。 DBIT-SEQ飞行员研究表明，MDD与CTRL中RNA剪接的变异性更高，RNA速度显示出高转录组 MDD中的不稳定性导致锥体神经元簇中的高病间异质性和表观遗传 ATAC分析确定了可能与MDD发病机理有关的标记。研究80 MDD和80 CTRL，年龄 14 - 90年，男性60％和40％的女性，猝死，剧烈的痛苦，清晰的毒理学，验尸后间隔<24小时，RNA完整性数（RIN）> 8，组织pH> 6，我们将：1。 MDD和CTRL应用HRMS。 2。在MDD中识别细胞簇的DEG与Ctrl海马，以应用SnRNA- SEQ和SNATAC-SEQ。 3.提供第一个海马空间转录组图集和表观基因组图集染色质可及性，识别特定区域的RNA动力学，并确定MDD与CTRL多组件应用DBIT-seq的差异。鉴定的海马细胞活力和功能的分子调节剂将为新的MDD处理提供了潜在的可药物靶标，以后在细胞和动物模型中进行测试。