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Identification of Epigenetics Correlates between Brain and Peripheral Tissues

大脑和周围组织之间表观遗传学相关性的鉴定

基本信息

批准号：
10333311
负责人：
Gen Shinozaki
金额：
$ 59.44万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-11 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10333311
关键词：
Address Age Amygdaloid structure Archives Autopsy Biological Markers Blood Brain Brain Diseases Brain region Cells Collaborations Collection Communities Complex DNA DNA Databases DNA Methylation Data Data Set Databases Depressed mood Development Diagnosis Disease Environment Epigenetic Process Excision Fluorescence-Activated Cell Sorting Functional disorder Future Genomic Segment Goals Hippocampus (Brain)Hot Spot Human Individual Iowa Lead Major Depressive Disorder Measures Mental disorders Methylation MicroRNAs Modification Neuroglia Neurons Neurosurgical Procedures Outcome Pathogenesis Pathology Patient Care Patient-Focused Outcomes Patients Peripheral Prefrontal Cortex Prevention Process Research Research Personnel Resected Resource Allocation Resources Saliva Sample Size Sampling Signal Transduction Swab Testing Time Tissue Sample Tissues Work biomarker discovery brain cell brain tissue cell type cohort epigenome epigenomics experience genome-wide high risk histone modification human tissue improved innovation interest large datasets methylation pattern neuropathology neurosurgery novel novel strategies prospective public health relevance research study sex specific biomarkers stressor therapy development trend

项目摘要

Abstract Psychiatric disorders such as major depressive disorder (MDD) are complex diseases where negative stressors increase the likelihood of its onset through epigenetic changes, such as DNA methylation (DNAm). Presently, disease-associated DNAm patterns of MDD have not been fully elucidated. This is in part due to the reliance of peripheral tissues such as blood, buccal cells, and saliva where it is unknown how DNAm changes from these tissues might be an accurate reflection of those changes in the brain. As such, there is an urgent need to provide a comprehensive database that would cross-compare DNAm patterns between the brain and other peripheral tissues to highlight candidate regions where disease-associated DNAm can be observed. To this end, our overall goal is to establish a comprehensive epigenomic database where DNAm patterns can be cross-compared between key brain regions (e.g., the hippocampus, amygdala, and dorsolateral prefrontal cortex), their neurons and glia components, and peripheral tissues. Our central hypothesis is that disease- associated DNAm will more likely reside in regions that vary in DNAm between different tissues. Our specific aims will address the following questions: In Aim 1, DNAm will be evaluated at a genome-wide level and cross- compared between brain and peripheral tissues to identify regions which have varying DNAm between tissues. In Aim 2, we will expand DNAm assessment in neuron and glia to the aforementioned key brain regions involved in MDD and compare that with peripheral tissues. In Aim 3, disease-associated DNAm regions will be evaluated using pathology-archived brain tissues from 206 MDD cases and 206 matched controls. This is the largest post-mortem study of MDD that specifically evaluates DNAm. Disease-associated DNAm will be overlaid with tissue-specific DNAm to determine regions where MDD-associated DNAm patterns will likely to occur. This proposed study is significant as it will provide a comprehensive epigenetic database that will guide researchers to candidate regions and suitable peripheral tissues to investigate DNAm changes in MDD. Its use may also be extended to other psychiatric disorders. This proposed study is innovative as it uses fresh brain, neuron, glia and peripheral tissues from the same individual to establish an epigenome database. It also uses disease-associated DNAm identified from a large cohort of post-mortem MDD brains to identify regions that are “hot-spots” for disease-associated methylation changes.

摘要精神障碍，如重度抑郁障碍(MDD)是一种复杂的疾病，在这种疾病中，应激源通过表观遗传变化增加其发病的可能性，如DNA甲基化(DNaM)。目前，MDD的疾病相关dNaM模式尚未完全阐明。这在一定程度上是由于依赖周围组织，如血液、口腔细胞和唾液，其中dNaM如何变化尚不清楚这些组织可能准确地反映了大脑的这些变化。因此，有一个紧急情况需要提供一个全面的数据库来交叉比较大脑和大脑之间的dNaM模式其他周围组织，以突出可观察到与疾病相关的dNaM的候选区域。至为此，我们的总体目标是建立一个全面的表观基因组数据库，其中dNaM模式可以大脑关键区域(例如，海马体、杏仁核和额叶背外侧)之间的交叉比较大脑皮层)、神经元和神经胶质成分以及外周组织。我们的中心假设是疾病- 相关的dNaM更可能存在于不同组织之间dNaM不同的区域。我们的特定 AIMS将解决以下问题：在AIMS 1中，dNaM将在全基因组水平上进行评估，并将在比较脑组织和周围组织之间的差异，以确定组织之间具有不同dNaM的区域。在目标2中，我们将把神经元和胶质细胞中的dNaM评估扩展到上述关键的大脑区域并与周围组织进行比较。在目标3中，与疾病相关的dNaM区域将使用206例MDD患者和206例匹配对照的病理档案脑组织进行评估。这是专门评估dNaM的MDD最大尸检研究。与疾病相关的dNaM将是覆盖特定于组织的dNaM，以确定MDD相关dNaM模式可能发生。这项拟议的研究具有重要意义，因为它将提供一个全面的表观遗传学数据库，将指导研究人员到候选区域和合适的外周组织来研究MDD中dNaM的变化。它的用法也可能延伸到其他精神障碍。这项拟议的研究具有创新性，因为它使用了新鲜的大脑，从同一个体的神经元、神经胶质细胞和外周组织建立表观基因组数据库。它还使用从大量死后MDD大脑队列中识别与疾病相关的dNaM，以确定与疾病相关的甲基化变化的“热点”。