Single-cell multi-omics of cerebellar dysregulation in schizophrenia and bipolar disorder

精神分裂症和双相情感障碍小脑失调的单细胞多组学

基本信息

批准号：
10348993
负责人：
Seth Abrams Ament
金额：
$ 27.04万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348993
关键词：
Address Anatomy Animal Model Area Autopsy Behavioral Biological Assay Bipolar Disorder Brain Brain imaging Brain region Cell Nucleus Cells Cellular Morphology Cerebellar vermis structure Cerebellum Chromatin Cognition Cytoplasmic Granules Data Data Set Disease Enhancers Family Fiber Gene Expression Gene Expression Profiling Gene Expression Regulation Genes Genetic Genetic Transcription Genomics Individual Knowledge Lead Link Mental disorders Modeling Neurocognitive Neuroglia Neurons Neurosciences Patients Psychiatric Diagnosis Public Health QTL Genes Quantitative Trait Loci Regulator Genes Resources Role Schizophrenia Small Nuclear RNA Structure Synapses System Tissue Sample Transposase XCL1 gene base brain tissue cell type differential expression effective therapy emotion regulation epigenomics gene network gene regulatory network gene repression genetic analysis genetic approach genome wide association study imaging study insight multiple omics neocortical network models neural circuit neurobiological mechanism neuropsychiatric disorder new therapeutic target novel therapeutics promoter public health relevance trait transcriptome transcriptome sequencing transcriptomics

项目摘要

Project Summary Neuropsychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BD) represent a substantial public health burden. The identification of disease-associated genes and gene networks has long been viewed as one of the most promising paths toward new therapies. In recent years, substantial progress has been made toward the discovery of these disease-associated genes through transcriptomic and epigenomic studies of post-mortem brain tissue. However, while SCZ and BD are associated with structural and functional changes in multiple cortical and sub-cortical brain regions, large-scale genomic studies have focused almost exclusively on a small number of neocortical areas. Several lines of evidence support an important role for the cerebellum in SCZ and BD, including results from brain imaging studies, anatomical studies, and gene expression profiling, and studies in animal models confirm important roles for the cerebellum in the regulation of emotional states and cognition. Here, we will perform single-nucleus RNA sequencing and single-nucleus chromatin accessibility assays to characterize associations of SCZ and BD with cell type-specific transcriptomic and epigenomic changes in the cerebellum (n=25 each for SCZ, BD, and non-diseased controls). Using these data, we will perform systems genetics analyses to predict “convergent neuroscience” mechanisms in the cerebellum, linking SNPs to genes to cell types to brain structure and function to psychiatric diagnoses.

项目概要精神分裂症 (SCZ) 和双向情感障碍 (BD) 等神经精神疾病代表了相当多的公众疾病相关基因和基因网络的识别长期以来被视为一种负担。近年来，在新疗法方面取得了实质性进展。通过死后的转录组和表观基因组研究发现这些疾病相关基因然而，虽然 SCZ 和 BD 与多种结构和功能变化有关。皮层和皮层下大脑区域，大规模基因组研究几乎完全集中在一个小的一些新皮质区域的证据支持小脑在 SCZ 和中的重要作用。 BD，包括脑成像研究、解剖学研究和基因表达谱以及研究的结果在动物模型中证实了小脑在情绪状态和认知调节中的重要作用。在这里，我们将进行单核 RNA 测序和单核染色质可及性测定，以表征 SCZ 和 BD 与细胞类型特异性转录组和表观基因组变化的关联小脑（SCZ、BD 和非疾病对照各 n=25）。我们将使用这些数据执行系统。遗传学分析预测小脑中的“趋同神经科学”机制，将 SNP 与基因联系起来细胞类型、大脑结构和功能、精神病学诊断。