Higher Order Chromatin and Genetic Risk for Alzheimer's Disease

高阶染色质和阿尔茨海默病的遗传风险

基本信息

批准号：
10317310
负责人：
Panagiotis Roussos
金额：
$ 166.54万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10317310
关键词：
3-Dimensional ATAC-seq Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease risk Appearance Architecture Autopsy Bioinformatics Biological Biological Assay Brain Cell Nucleus Cells Cellular Assay Cellular Indexing of Transcriptomes and Epitopes by Sequencing Chimeric Proteins Chromatin Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collection Communities Data Data Analyses Data Analytics Dementia Development Disease Disease Progression Dissection Enhancers Evaluation Fluorescence Future Gene Expression Gene Expression Profiling Genes Genetic Genetic Risk Genetic Variation Genome Genomics Genotype Goals Grant Human Impaired cognition Individual Late-Onset Disorder Lead Lesion Libraries Link Maps Mediating Microglia Molecular Molecular Disease Neurons Nuclear Nucleic Acid Regulatory Sequences Outcome Output Pathogenesis Phenotype Population Proxy Regulation Regulator Genes Regulatory Element Reporter Research Risk Factors Sampling Secondary to Small Nuclear RNA Sorting - Cell Movement Superior temporal gyrus Symptoms Testing Transcript Untranslated RNA Variant Work base brain tissue case control causal variant cell type cohort disease mechanisms study disorder control entorhinal cortex epigenome genetic risk factor genome wide association study genome-wide genomic signature induced pluripotent stem cell insight molecular marker multidisciplinary multimodality non-genetic novel strategies programs progressive neurodegeneration promoter risk variant single-cell RNA sequencing therapeutic development three dimensional structure transcriptome transcriptome sequencing

3-Dimensional ATAC-seq Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease risk Appearance Architecture Autopsy Bioinformatics Biological Biological Assay Brain Cell Nucleus Cells Cellular Assay Cellular Indexing of Transcriptomes and Epitopes by Sequencing Chimeric Proteins Chromatin Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collection Communities Data Data Analyses Data Analytics Dementia Development Disease Disease Progression Dissection Enhancers Evaluation Fluorescence Future Gene Expression Gene Expression Profiling Genes Genetic Genetic Risk Genetic Variation Genome Genomics Genotype Goals Grant Human Impaired cognition Individual Late-Onset Disorder Lead Lesion Libraries Link Maps Mediating Microglia Molecular Molecular Disease Neurons Nuclear Nucleic Acid Regulatory Sequences Outcome Output Pathogenesis Phenotype Population Proxy Regulation Regulator Genes Regulatory Element Reporter Research Risk Factors Sampling Secondary to Small Nuclear RNA Sorting - Cell Movement Superior temporal gyrus Symptoms Testing Transcript Untranslated RNA Variant Work base brain tissue case control causal variant cell type cohort disease mechanisms study disorder control entorhinal cortex epigenome genetic risk factor genome wide association study genome-wide genomic signature induced pluripotent stem cell insight molecular marker multidisciplinary multimodality non-genetic novel strategies programs progressive neurodegeneration promoter risk variant single-cell RNA sequencing therapeutic development three dimensional structure transcriptome transcriptome sequencing

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项目摘要

PROJECT SUMMARY Alzheimer's disease (AD) is the most common form of dementia and is characterized by cognitive impairment and progressive neurodegeneration. Genome-wide association studies of AD have identified more than 30 risk loci; however, a major challenge in the field is that the majority of these risk factors are harbored within non- coding regions where their impact on AD pathogenesis has been difficult to establish. Therefore, the molecular basis of AD development and progression remains elusive and, so far, reliable treatments have not been found. AD-associated changes in the regulation of the epigenome can result from primary genetic and non-genetic causal factors and epiphenomena, including changes secondary to disease progression. Thus, the epigenome is a strong proxy marker to study late-onset diseases such as AD, where there can be a gap of multiple decades between initiation of disease progression and the appearance of symptoms. In the original R01 grant titled “Higher Order Chromatin and Genetic Risk for Alzheimer's Disease”, we expanded the panel of molecular markers in the Mount Sinai Brain Bank AD cohort by generating cell type-specific (neurons and non-neurons) ATACseq in the entorhinal cortex and superior temporal gyrus of AD cases and controls. By doing so, we identified shared and distinct regulatory genomic signatures associated with clinical dementia and neuropathological lesions and with early and late stages of AD. Overlap with AD common risk variants identified primary chromatin accessibility perturbations that are driven by genetic variation, compared to secondary changes with no apparent genetic origin. The overarching goal of this proposal is to address the limitations of our previous research by examining and validating AD-related changes on chromatin accessibility and the 3D genome at the single cell level. Based on recent data from our group and others, we hypothesize that genotype-phenotype associations in AD are causally mediated by cell type-specific alterations in the regulatory mechanisms of gene expression. To test our hypothesis, we propose the following Specific Aims: (1) perform multimodal (i.e., within cell) profiling of the chromatin accessibility and transcriptome at the single cell level to identify cell type-specific AD-related changes on the 3D genome; (2) fine-map AD risk loci to identify causal variants, regulatory regions and genes; (3) functionally validate putative causal variants and regulatory sequences using novel approaches that combine massively parallel reporter assays, CRISPR and single cell assays in neurons and microglia derived from induced pluripotent stem cells; and (4) develop and maintain a community workspace that provides for the rapid dissemination and open evaluation of data, analyses, and outcomes. Overall, our multidisciplinary computational and experimental approach will provide a compendium of functionally and causally validated AD risk loci that has the potential to lead to new insights and avenues for therapeutic development.

项目摘要阿尔茨海默氏病（AD）是痴呆症的最常见形式，其特征是认知障碍和进行性神经变性。全基因组关联研究已确定30多个风险位点；但是，该领域的一个主要挑战是，这些危险因素中的大多数是在非 - 很难确定它们对AD发病机理的影响的编码区域。因此，分子广告发展和进步的基础仍然难以捉摸，到目前为止，可靠的治疗尚未成立。表观遗传组调节的广告相关变化可能是由原发性遗传和非遗传的变化因果因子和表现瘤，包括疾病进展的继发的变化。那，表观基因组是研究较晚发病疾病（例如AD）的强大代理标记，其中可能存在多个差距疾病进展的启动与症状出现之间的数十年。在原始R01赠款中我们的标题为“高阶染色质和阿尔茨海默氏病的遗传风险”，我们扩大了分子面板通过产生细胞类型特异性（神经元和非神经元），在西奈山脑库山广告组中的标记物 Atorhinal皮层中的Atacseq和AD病例和对照的上临时回。这样，我们确定了与临床痴呆和神经病理病变以及AD的早期和晚期。与广告公共风险变体重叠相比次要变化没有明显的遗传来源。该提案的总体目标是通过检查我们先前研究的局限性并在单细胞水平上验证了染色质可及性和3D基因组的与AD相关的变化。根据我们小组和其他人的最新数据，我们假设AD中的基因型 - 表型关联不幸的是，基因表达的调节机制中的细胞类型特异性改变介导。到检验我们的假设，我们提出以下特定目的：（1）执行多模式（即在细胞内）的分析染色质的可访问性和单细胞级的转录组，以识别特定于AD相关的单元格类型 3D基因组的变化；（2）局部局部验证局部鉴定因果变异，调节区域和基因的风险；（3）使用新方法来验证推定的因果变异和调节序列在神经元和小胶质细胞中的大规模平行记者测定，CRISPR和单细胞测定从诱导的多能干细胞中；（4）开发和维护一个社区工作空间，以提供快速传播和公开评估数据，分析和结果。总体而言，我们的多学科计算和实验方法将提供功能上，有时经过验证的AD的汇编风险基因座有可能导致治疗发展的新见解和途径。