权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Programming of Resident Macrophages by the Brain Environment Following Transplantation

移植后大脑环境对常驻巨噬细胞的编程

基本信息

批准号：
10790219
负责人：
Frederick Bennett
金额：
$ 47.54万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-16 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10790219
关键词：
ATAC-seq Adopted Adoption Atlases Automobile Driving Back Biological Blood Brain Brain Diseases Cells Cellular biology Complex Data Development Disease Engraftment Environment Epigenetic Process Exposure to Fingerprint Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Goals Growth Harvest Homeostasis Immune In Vitro Infiltration Injections Knowledge Kupffer Cells Link Liver Macrophage Maps Measures Methods Microglia Modeling Molecular Morphology Neuroglia Pathogenesis Pathway interactions Peripheral Process RNA Regulation Resolution Rest Role Sex Differences Shapes Signal Transduction Specific qualifier value Testing Time Transplantation brain parenchyma cell type chemotherapy data resource epigenomics genetic signature improved in vivo in vivo Model monocyte nervous system disorder neurotransmission new therapeutic target prevent programs receptor response sex single cell analysis single cell sequencing single-cell RNA sequencing therapy development transcription factor transcriptomics

项目摘要

PROJECT SUMMARY A striking feature of microglia, the brain's resident macrophages, is their ability to adapt in response to changes in the brain environment. Microglial state changes occur in development and nearly all diseases, often linked to harmful or helpful functions. A better understanding of the regulatory mechanisms underlying microglia state change will therefore improve understanding of brain diseases, and uncover new therapeutic targets. Dozens of disease reactive states have been identified, but little is known about how microglia transition between them. Even microglial “homeostasis” is a state actively maintained by brain environmental signals, and lost in a culture dish. We are experts in the isolation and manipulation of microglia, and created a unique model for intracranial transplantation of microglia and other macrophages following genetic microglia depletion. After transplantation, macrophages engraft the brain and over 14 days undergo dramatic changes in gene expression. In preliminary data, we harvested transplanted macrophages at several timepoints, and by single cell RNA sequencing (scRNAseq), measured the progressive acquisition of microglial identity over time. With this highly controlled in vivo model, we will generate a comprehensive fingerprint of how transplanted microglia are programmed by the brain environment, and use it to identify the genes, pathways, regulatory networks likely to be responsible. In aim 1A, we will capture the environmental programming of cultured microglia after transplant, using paired single cell RNA/ATACseq to identify intermediate states, and to predict the external signals, transcription factors, receptors, pathways and networks responsible. In aim 1B, we will compare transplantation with all combinations of donor and host sex, in order to determine its role in microglia identity specification. Finally, since blood infiltrating macrophages can resemble microglia but remain a distinct cell type, aim 2 will measure their programming after transplantation, to better understand why they cannot become microglia. In summary, completion of these aims will fill knowledge gaps about the regulation of microglial state and identity, create a new foundational data resource, and substantiate an R01 proposal to causally test identity regulators uncovered here.

项目总结