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.

Public Health Relevance

Alzheimer?s disease (AD) is the most common form of dementia and the sixth leading cause of death in the United States. We propose to use the latest single cell proteomics technologies to investigate the dynamics of diverse cell populations in AD models, and to decipher and validate leading targets in dynamic cell-cell interaction and AD pathogenesis using human AD cases, as well as mouse and human organoids models.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
1RF1AG068581-01
Application #
10046195
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2020-09-15
Project End
2024-08-31
Budget Start
2020-09-15
Budget End
2024-08-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105