Identification and Characterization of Cell-Specific Transposable Elements Implicated on Alzheimer Disease and Healthy Aging

与阿尔茨海默病和健康衰老相关的细胞特异性转座元件的鉴定和表征

基本信息

批准号：
10677894
负责人：
Carlos Cruchaga
金额：
$ 180.99万
依托单位：
WASHINGTON 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：
2022-08-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677894
关键词：
ATAC-seq Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk American Amyloid beta-Protein Biological Models Biology Brain Cell model Cells ChIP-seq Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Collection Complex DNA Methylation DNA Transposable Elements Data Dementia Disease Event Fibroblasts Functional disorder Genes Genetic Genetic Transcription Genetic study Genome Genomic Instability Genomic approach Genomics Goals Human Human Genome Human Resources Individual Inflammation Lead Location Maps Mediator Microglia Mobile Genetic Elements Modeling Molecular Mutation Nerve Degeneration Neurons Pathogenesis Pathogenicity Pathology Pathway interactions Repetitive Sequence Role Sampling Senile Plaques Small Interfering RNA TREM2 gene Tauopathies Tissue Model Toxic effect Transcript Variant abeta accumulation amyloid precursor protein processing brain cell brain tissue cell type cohort differential expression effective therapy extracellular genetic element genetic variant genome editing healthy aging human model human stem cells immune function induced pluripotent stem cell interdisciplinary approach knock-down neuroinflammation neuron loss novel novel strategies overexpression presenilin-1 presenilin-2 rare variant response risk variant tau Proteins tau-1 therapeutic target transcriptome transcriptome sequencing transcriptomics

项目摘要

Abstract Alzheimer disease (AD) is the most common form of dementia and neurodegeneration affecting more than 5 million Americans with no current effective treatment. Several Mendelian mutations and risk variants have been identified. We and others have shown that AD is associated with changes in brain cell proportion and transcriptomic changes, some of them are also cell specific. Additionally, the latest genetic studies implicate cell-specific pathogenic events that lead to disease. Pathogenic variants in APP, PSEN1 and PSEN2 affects APP processing leading to Aβ aggregates and neuronal death. Genetic variants in TREM2 and MS4A modify AD risk by affecting microglia activity. To fully understand and characterize the role of transposable elements (TE) in AD pathogenesis there is a need to novel and multidisciplinary approaches. Here we will combine novel genomic approaches in human brain tissues, direct converted neurons and iPSC-derived microglia (iMGL) to identify cell-specific TE and downstream (chromatin accessibility, transcription) changes implicated in AD. We will leverage a large and unique resources of human brain samples and fibroblast from individuals with mutations in APP, PSEN1, PSEN2, as well as risk variants in TREM2, MS4A or APOE. We will also use the direct converted neurons and iMGL, together with new genomic editing approaches to target and characterize the mechanism by which TE contribute to disease.

抽象的阿尔茨海默氏病（AD）是痴呆和神经退行性的最常见形式，影响超过5 百万美国人没有目前的有效治疗。几个孟德尔突变和风险变体具有我们和其他人表明，AD与脑细胞比例的变化有关，转录组变化，其中一些也是细胞特异性的。此外，最新的遗传研究隐含导致疾病的细胞特异性病原事件。 APP，PSEN1和PSEN2中的致病变异会影响应用程序处理导致Aβ聚集体和神经元死亡。 TREM2和MS4A修改中的遗传变异通过影响小胶质细胞活性来风险。充分理解和表征可旋转元素的作用（TE）在AD发病机理中，需要采用新颖和多学科的方法。在这里，我们将结合小说人脑组织中的基因组方法，直接转化的神经元和IPSC衍生的小胶质细胞（IMGL）识别与AD有关的特定细胞特异性TE和下游（染色质可及性，转录）变化。我们将利用人类脑样本的大量资源，以及来自 APP，PSEN1，PSEN2以及TREM2，MS4A或APOE中的风险变体中的突变。我们还将使用直接转换神经元和IMGL，以及新的基因组编辑方法来靶向和表征 TE促进疾病的机制。