Programming of Resident Macrophages by the Brain Environment Following Transplantation
Programming of Resident Macrophages by the Brain Environment Following Transplantation
批准号:
10790219
负责人:
Frederick Bennett
金额:
$47.54万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-16 至 2025-08-31
关键词:
ATAC-seqAdoptedAdoptionAtlasesAutomobile DrivingBackBiologicalBloodBrainBrain DiseasesCellsCellular biologyComplexDataDevelopmentDiseaseEngraftmentEnvironmentEpigenetic ProcessExposure toFingerprintGene ExpressionGene Expression ProfileGenesGeneticGenetic TranscriptionGoalsGrowthHarvestHomeostasisImmuneIn VitroInfiltrationInjectionsKnowledgeKupffer CellsLinkLiverMacrophageMapsMeasuresMethodsMicrogliaModelingMolecularMorphologyNeurogliaPathogenesisPathway interactionsPeripheralProcessRNARegulationResolutionRestRoleSex DifferencesShapesSignal TransductionSpecific qualifier valueTestingTimeTransplantationbrain parenchymacell typechemotherapydata resourceepigenomicsgenetic signatureimprovedin vivoin vivo Modelmonocytenervous system disorderneurotransmissionnew therapeutic targetpreventprogramsreceptorresponsesexsingle cell analysissingle cell sequencingsingle-cell RNA sequencingtherapy developmenttranscription factortranscriptomics
中文摘要
项目总结
英文摘要
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.
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海外基金