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.

抽象的阿尔茨海默病 (AD) 是最常见的痴呆症和神经退行性疾病，影响超过 5 种疾病数百万目前尚无有效治疗方法的美国人患有多种孟德尔突变和风险变异。我们和其他人已经证明 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。导致疾病的细胞特异性致病事件。 APP 处理导致 Aβ 聚集和神经死亡 TREM2 和 MS4A 修饰中的遗传变异。通过影响小胶质细胞活性来充分了解和表征转座因子的作用。 (TE) AD 发病机制需要新颖的多学科方法。人类脑组织中的基因组方法，直接将神经元和 iPSC 衍生的小胶质细胞 (iMGL) 转化为识别 AD 中涉及的细胞特异性 TE 和下游（染色质可及性、转录）变化。将利用大量独特的人脑样本资源和来自患有此类疾病的个体的成纤维细胞 APP、PSEN1、PSEN2 的突变，以及 TREM2、MS4A 或 APOE 的风险变异。直接转换的神经元和 iMGL，以及新的基因组编辑方法来定位和表征 TE 导致疾病的机制。