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Single-nuclei multiomic analysis of DLB progression

DLB 进展的单核多组学分析

基本信息

批准号：
10503442
负责人：
YOON-SEONG KIM
金额：
$ 176.09万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
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：
2022-08-17 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10503442
关键词：
ATAC-seq Age Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amygdaloid structure Astrocytes Autopsy Bar Codes Brain Brain Stem Brain region Cell Nucleus Cells Chromatin Chromium Data Data Analyses Dementia Dementia with Lewy Bodies Disease Disease Progression Dissection Endothelial Cells Ensure Epigenetic Process Etiology Freezing Funding Opportunities Gender Gene Expression Gene Expression Profiling Genes Genomics Goals Histones Immunohistochemistry Lewy Bodies Lewy Body Disease Lymphocyte Microglia Molecular Neurodegenerative Disorders Neurons Oligodendroglia Oncogene Deregulation Parkinson Disease Parkinson&apos s Dementia Pathogenesis Pathologic Pathology Patients Peripheral Post-Translational Protein Processing Prevalence Process RNA Regulator Genes Reporting Research Sampling Senile Plaques Small Nuclear RNA Staging Staging System Stains Substantia nigra structure Techniques Tissue-Specific Gene Expression Tissues United States National Institutes of Health Validation XCL1 gene alpha synuclein attenuation brain tissue cell type data analysis pipeline disorder control domain mapping epigenomics frontal lobe histone modification hyperphosphorylated tau improved innovation innovative technologies insight large datasets multiple omics neocortical neurodegenerative dementia novel strategies power analysis promoter protein TDP-43 sex single cell analysis skills synucleinopathy tissue resource transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY Dementia with Lewy body (DLB) has been historically under-investigated relative to its prevalence as most studies of synucleinopathies focus on PD and PDD. Accumulating evidence indicates, however, DLB is a distinct age-associated neurodegenerative dementia. Like PD, various types of cells including neurons, microglia, astrocytes, oligodendrocytes, endothelial cells, and peripheral lymphocytes might contribute to DLB pathogenesis. To understand complexities of DLB pathogenesis, more comprehensive approaches to investigating different cell types and multiple brain regions over the course of disease progression are necessary. Our lab has put extensive effort into single-nuclei analysis of postmortem brain tissues using a recently released Chromium Single-Cell Multiome ATAC plus Gene Expression platform (10X Genomics) and successfully established all key techniques and a data analysis pipeline. To track the progression of disease using both RNA- and ATAC-seq data in the same cell, we have developed a novel strategy: “correlated pseudo-pathogenesis (cPP)” trajectory analysis. We also established “gene-peak” analysis allowing us to analyze relationships between gene expression and chromatin accessibility in a single cell. Our technical advancements and innovative data analysis skills will satisfy this FOA requesting “projects to identify cellular changes in ADRD post- mortem brain tissue across disease progression.” To achieve the goal set by the current FOA, we will pursue the following aims: Aim 1. Neuropathological staging of DLB and validation of control postmortem samples. Postmortem brain tissues from the HBTRC will be further validated for neuropathological staging by H&E and α- SYN immunohistochemical staining according to Unified Staging System for Lewy Body Disorders (USSLB). To eliminate incidental Lewy body disease (ILBD), control tissues will also be investigated for α-SYN pathology. Aim 2. Isolate nuclei from each sample and perform snRNA-seq and snATAC-seq analysis. 4 brain regions from three groups: 1) control; 2) stage II (limbic or brainstem predominant)/III (both limbic and brainstem); 3) and stage IV (neocortical), will be subject to single-nuclei multiomic analysis. Aim 3. Spatial transcriptomic analysis for topological domain mapping. Differential gene expression in the specific microdomains of each brain region and relationship to α-SYN pathology will be investigated using a spatially barcoded gene expression profiling array.

项目总结