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Epigenomic analysis of neural circuits in Alzheimer's disease mouse models

阿尔茨海默病小鼠模型神经回路的表观基因组分析

基本信息

批准号：
10615701
负责人：
Bing Ren
金额：
$ 74.88万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615701
关键词：
ATAC-seq Affect Age Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease model American Amyloid Beta A4 Precursor Protein Amyloid beta-Protein Animals Architecture Atlases Back Behavior Behavior Therapy Behavioral Cell Nucleus Cells Chromatin Chromosomes Coupled DNA Methylation DNA mapping DNA methylation profiling Data Defect Dementia Development Disease Disease Progression Dominant-Negative Mutation Drug Targeting Elderly Exhibits Gene Expression Gene Expression Profile Genes Genetic Transcription Genomics Goals HDAC3 gene Health Hippocampus Histone Deacetylase Inhibitor Human Impaired cognition Impairment Joints Knock-in Learning Location Maps Measures Memory Memory Loss Modeling Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurons Pathogenesis Pathway interactions Performance Physical Exercise Physiology Population Publishing Regulator Genes Research Running Shapes Technology Testing Untranslated RNA Wild Type Mouse Work age related behavior change brain health brain tissue cell type design diagnostic tool drug candidate early detection biomarkers effective therapy epigenome epigenomics exercise intervention histone modification imaging approach improved in vivo calcium imaging inhibitor intervention effect middle age molecular marker mouse model multiple omics mutant neural neural circuit neuropathology neuroregulation new therapeutic target novel therapeutic intervention optogenetics programs response sedentary single nucleus RNA-sequencing targeted biomarker transcriptome transcriptome sequencing

项目摘要

Project Summary / Abstract Alzheimer’s disease (AD) is the most common cause of progressive dementia (memory and cognitive loss) in older adults. Presently, more than 5.5 million Americans may have dementia caused by AD. There is no cure for this debilitating condition. It is increasingly critical that we develop better early diagnostic tools and new treatment strategies for this neurodegenerative disease. Previous gene expression studies using brain tissue and cross-sectional design identify genes whose expression correlates with AD progression. Gene expression is regulated by the cell’s epigenome comprising of DNA methylation, histone modification and non- coding RNAs. We propose to characterize the epigenome of key cell types in neural circuits responsible for learning and memory. Our goal is to determine how the epigenome shapes hippocampal circuit activity and behaviors during AD progression, using the latest single cell genomic technologies coupled with functional circuit mapping and behavioral analysis. We will use two AD mouse models that recapitulate neuropathological features and functional defects observed in human Alzheimer’s. Our guiding hypothesis is that AD neurodegeneration causes significant alterations in the epigenome of cells, including maladaptive changes in accessible chromatin landscape and gene expression programs in disease relevant cell types. This in turn causes defects in specific neural circuit functionality during AD pathogenesis. In Aim 1, we will generate a comprehensive epigenome- and transcription-based cell atlas for hippocampal CA1 and subiculum, and identify epigenomic changes that accompany AD progression in each cell type in AD model mice and age-matched control mice. Single nucleus ATAC-seq (snATAC-seq), single nucleus RNA-seq (snRNA-seq) and the newly developed Methyl-HI in single cells for joint mapping of DNA methylation and chromatin contacts will be key approaches. The proposed work will allow for creation of the first single cell multi-omics atlas of the hippocampal circuits, and will allow us to track the epigenomic changes exhibited by multiple specific cell populations at different AD-like neurodegeneration stages. In Aims 2 and 3, we will investigate the cell subtype specific epigenomic and gene expression basis of neural circuit activities and related memory behaviors in AD model mice of middle age. We will measure epigenomic and behavioral changes in response to genetically targeted ontogenetic hippocampal circuit manipulation and histone deacetylase inhibition. Further, we will determine the beneficial effects of simple behavioral interventions via physical exercise on AD-related epigenomic signatures in Aim 3. Together, our proposed research will provide a new framework to study the molecular underpinnings of neural circuit activities affected during the course of AD pathogenesis. It will also lead to the identification of new therapeutic targets and molecular biomarkers for early detection and better treatment of AD.

项目摘要/摘要