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Clonal dynamics of the blood stem cell niche

Clonal dynamics of the blood stem cell niche
血液干细胞生态位的克隆动力学
批准号:
10569876
负责人:
Chloe Sophie Baron
金额:
$9.15万
依托单位:
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:
2023-07-01 至 2025-06-30
关键词:
APLN geneAdultAdvisory CommitteesAffectAlgorithmsAutomobile DrivingAwardBar CodesBiochemicalBiological AssayBloodBlood CellsBlood VesselsBone MarrowCRISPR/Cas technologyCell MaintenanceCell ProliferationCellsClonalityClone CellsColorComputer AnalysisComputing MethodologiesConfocal MicroscopyDNADataData SetDiseaseDisease ProgressionDisease modelDysmyelopoietic SyndromesEmbryonic DevelopmentEndothelial CellsEndotheliumEquilibriumFeedbackFibroblastsFlow CytometryGene Expression ProfileGeneticGenetic TranscriptionGoalsHematological DiseaseHematopoiesisHematopoieticHematopoietic stem cellsHeterogeneityHormone secretionHumanIn VitroJournalsKidneyKnowledgeLaboratoriesLigandsMarrowMediatingMentorshipMethodsMicroscopicModelingMolecularMusMutagenesisOrganismOutputPathogenesisPathway interactionsPlayPrizeProliferatingProto-OncogenesRecoveryReporterResearchResearch PersonnelRoleScienceSignal PathwaySignal TransductionStromal CellsTechnical ExpertiseTechnologyTestingTransgenic OrganismsTransplantationVascular PermeabilitiesVascular remodelingVisualizationWorkZebrafishadrenomedullinangiogenesisc-myc Genescancer cellcandidate identificationcareercareer developmentcell typecomputational basisconfocal imaginghematopoietic stem cell nicheimprovedin silicoin vivoin vivo evaluationmosaicmouse modelmultidisciplinarymultiple omicsnew therapeutic targetnext generation sequencingnoveloverexpressionpreventprogenitorprogramspromoterreceptorreflectance confocal microscopyresearch and developmentresponsesingle cell mRNA sequencingstemstem cell biologysymposiumtooltranscriptometranscriptomics

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PROJECT SUMMARY The mechanisms by which the hematopoietic stem and progenitor (HSPC) niche is affected by clonal hematological disorders such as myelodysplastic syndrome (MDS) remain poorly understood. Furthermore, the heterogeneity and clonal response of endothelial and stromal cells (the main components of the HSPC niche) in MDS in vivo remain unexplored. To tackle these aspects, I developed a new zebrafish model of MDS by driving the protooncogene CMYC overexpression specifically in blood cells. Additionally, I crossed a genetic lineage tracing zebrafish line called GESTALT to a double transgenic zebrafish line carrying two fluorescent reporters allowing to purify specifically niche endothelial and stromal cells. This way, I created a new GESTALT line that permits CRISPR-CAS9 based barcoding during zebrafish embryonic development, purification of adult marrow niche cells and recovery of niche DNA barcodes by sequencing. Combining these novel tools, I induced MDS in barcoded zebrafish and read out the clonality and the transcriptome of endothelial and stromal cells. I discovered that clones of stromal cells selectively expand, and endothelial cells are transcriptionally remodeled in MDS. Given these data, I hypothesize that MDS remodels the clonality and transcriptional profile of the HSPC niche and that mechanisms involved in HSPC-niche interactions promote disease progression. Under the mentorship of Dr. Leonard Zon, I will investigate the mechanisms by which MDS remodels the niche using a combination of in silico computational approaches, genetic (GESTALT) and color based (Zebrabow) lineage tracing, confocal microscopy and in vivo mosaic mutagenesis. Once I establish my laboratory, I will build a multidisciplinary team to deepen my computational analyses and broaden my in vivo genetic and biochemical perturbations of the clonal mechanisms of niche involvement in MDS. My overarching goal is to identify novel targetable mechanisms specific to the HSPC niche that would prevent and/or halt MDS progression. This K99/R00 award will enable me to develop new technical skills, participate in courses that will improve my ability to manage a laboratory, and attend conferences that will broaden my network and my knowledge of hematological disease modeling, Zebrabow lineage tracing paired with confocal microscopy and zebrafish mutagenesis. The scientific advisory committee I have put together includes experts in the fields of hematopoiesis, lineage tracing, and stem cell biology and, along with Dr. Zon, will give me feedback on my research and career progress. These proposed research and career development activities will pave the way for me to become an independent investigator discovering and studying new mechanisms responsible for hematopoietic disorders progression mediated by the blood stem cell niche.
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