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Dissecting neuron-microglia-astrocyte interaction in AD pathogenesis

解析 AD 发病机制中神经元-小胶质细胞-星形胶质细胞的相互作用

基本信息

批准号：
10046195
负责人：
JUNMIN PENG
金额：
$ 495.03万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
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：
2020-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10046195
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amino Acids Animal Model Animals Astrocytes Autophagocytosis Brain Candidate Disease Gene Cause of Death Cell Communication Cells Complex Data Data Set Dementia Development Disease Event Female Functional disorder Genes Genetic Transcription Genetic study Genotype Goals Human In Situ Investigation Knock-in Knowledge Label Mass Spectrum Analysis Measures Mediating Microglia Modeling Molecular Molecular Profiling Mouse Protein Mus Neurons Organoids Outcome Pathogenesis Pathology Pathway interactions Peptide Hydrolases Physiologic pulse Physiological Population Protein Dynamics Proteins Proteome Proteomics Protocols documentation RNA Sampling Signal Transduction Specimen System Systems Biology TREM2 gene Technology Ubiquitin United States Validation Work age related base brain tissue cell type effective therapy hTau Mice male mouse model multiple omics novel novel therapeutic intervention protein degradation protein function secretory protein sex transcriptome transcriptomics transgene expression

项目摘要

PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to understand the age-related, neuron-microglia-astrocyte-specific proteome dynamics and interaction in the brain and their deregulation in the pathogenesis of Alzheimer’s disease (AD). Our ongoing large-scale profiling of transcriptome and proteome in bulk AD brain tissue have revealed that the transcriptome is often not an accurate indicator of protein abundance, due to posttranscriptional events, such as protein turnover. Genetic studies have revealed over 20 AD-related genes, many of which are associated with specific cell types. We hypothesize that dysfunction of neuron-microglia-astrocyte interaction contributes to AD pathogenesis, and propose to use the latest cutting edge technologies to profile cell type specific proteome, in situ transcriptome, and proteome turnover in the three cell populations from multiple common AD-related mouse models, to decipher molecular signaling networks in disease development, and to validate targets in human AD cases, mouse models, and human organoid models. Three specific aims are: (i) to disentangle dynamic neuron- microglia-astrocyte-specific proteome and interaction in AD mice by BONCAT-mediated single cell type proteomics and spatial transcriptomics, (ii) to measure cell type-specific proteome-wide protein turnover in AD by BONCAT pulse-chase analysis, and (iii) to study deregulation of proteome dynamics in human AD cases, mouse models and brain organoids. Successful outcome of this project will identify novel, cell type specific molecular components and pathways regulating cell-cell interactions during AD pathogenesis, which may provide new therapeutic strategies for effective treatment of this devastating disorder.

项目总结/文摘