Mechanisms of Flow-driven Transcriptional Control of Hematopoietic Stem Cell Development by YAP
YAP 流驱动转录控制造血干细胞发育的机制
基本信息
- 批准号:10283499
- 负责人:
- 金额:$ 15.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AchievementAddressAdultAdvisory CommitteesAlgorithmsAnimalsAortaArteriesAwardBehaviorBloodBlood CellsBlood VesselsBlood flowBostonCandidate Disease GeneCell NucleusCellsCellular biologyChemicalsClinicalComplexCoupledCouplingCuesDNADNA BindingDNA-Protein InteractionDataDevelopmentDistantDorsalEmbryoEmbryonic DevelopmentEndothelial CellsEndotheliumEnhancersEnvironmentErythroidEventExhibitsFetal LiverFishesFutureGene ExpressionGenerationsGenesGeneticGenetic TranscriptionGoalsGrowthGrowth and Development functionHematological DiseaseHematologyHematopoiesisHematopoieticHematopoietic Cell ProductionHematopoietic NeoplasmsHematopoietic Stem Cell SpecificationHematopoietic Stem Cell TransplantationHematopoietic SystemHematopoietic stem cellsHomeHumanImageImmuneIn VitroIndividualIntegrin beta ChainsIntegrinsInvestigationLaboratoriesLearningLinkLogicLymphoidMammalsMechanicsMediatingMediator of activation proteinMembraneMembrane ProteinsMentorsMentorshipMethodsMolecularMorphogenesisMorphologyMyelogenousNuclearOrganismPatientsPediatric HospitalsPeriodicityPhasePhenotypePiezo 1 ion channelPiezo ion channelsPostdoctoral FellowProductionProtein Activation PathwayProteinsProtocols documentationRUNX1 geneRegulationRegulator GenesResearchResearch TrainingScientistSignal TransductionSignaling ProteinSolidStem Cell DevelopmentStretchingSystemTherapeuticTherapeutic UsesTissuesTrainingTranscriptional RegulationTranslationsTransplantationViscosityWorkZebrafishcareer developmentcell typechemical geneticscofactordevelopmental geneticsendothelial stem cellgenetic manipulationgenome-widehematopoietic differentiationhematopoietic genehematopoietic stem cell differentiationhematopoietic stem cell expansionhematopoietic stem cell fatehematopoietic stem cell formationhematopoietic tissuehemodynamicshemogenic endotheliumimprovedin vivoin vivo evaluationinduced pluripotent stem cellinterestknock-downleukemialeukemia/lymphomalink proteinmechanical forcemedical schoolsnew technologynon-geneticnovelprogramsprotein activationresponseself-renewalshear stressstem cell biologystem cell therapysuccesstranscription factortranscriptomicsvertebrate embryos
项目摘要
Project Summary/Abstract
Hematopoietic stem cells (HSCs) are capable of producing all erythroid, myeloid and lymphoid blood
cells of an organism. Coupled with their unique capacity for self-renewal, successful transplantation of healthy
HSCs is the only therapy currently available that can completely replace and restore the blood system in patients
with leukemia and lymphoma. Despite this need, HSCs presently cannot be efficiently created or cultured in vitro,
suggesting that extrinsic factors supporting their growth and development in vivo are lacking from existing
protocols. Previous work from our lab demonstrated that blood flow is an essential non-genetic environmental
cue required for HSC production in vertebrate embryos, mediated in part by stimulating mechanical activation of
the Yes-associated protein (YAP) transcription factor (TF). This proposal intends to resolve the physical, genetic
and molecular mechanisms underlying mechanically-activated, YAP-driven HSC production. YAP, while a potent
co-activator of gene expression, lacks DNA-binding ability of its own. To understand the molecular logic behind
flow/YAP-driven hematopoiesis, the goal of the first aim is to employ chemical, physical and genetic perturbation
of shear stress and cyclic stretch in live zebrafish embryos to assess the impact of these individual components
of hemodynamic force on HSC production from hemogenic endothelium (HE). To this will be added tissue-
specific transcriptomic and genome-wide YAP/DNA interaction profiling from sorted HE from wildtype zebrafish,
flow-deficient and yap-/- animals (with normal blood flow) in order to discriminate flow-dependent gene regulatory
modules and transcriptional targets that rely on YAP. Hypothesis-driven candidate TFs will be tested in vivo and
in vitro to evaluate YAP-interaction ability and uncover key partners required for normal YAP-dependent
hematopoiesis. In the second aim, the zebrafish system will be used to investigate candidate membrane-
localized proteins, Piezos and Integrins, as components linking hemodynamic forces with YAP activation. These
studies stand to provide a comprehensive “membrane-to-nucleus” paradigm for how blood flow activates YAP
to guide developmental hematopoiesis, which may improve current efforts to generate or expand HSCs.
As a postdoctoral fellow, Dr. Sugden will conduct his research in the laboratory of Dr. Trista North at
Boston Children's Hospital. Her expertise in extrinsic regulation of developmental hematopoiesis, together with
dedicated co-mentorship by Dr. George Daley (an expert in stem cell biology and hematology) and a strong
advisory team provide an exceptionally well-supported environment for career development and research
training. Dr. Sugden will build on a solid background in developmental genetics and live-imaging, by adding new
technologies in transcription factor/DNA interaction profiling, transcriptomics and in vitro methods to study protein
interactions. A rigorous research and training plan lay the groundwork for success, both in the mentored and
independent phases of the award. The environment at Boston Children's Hospital and Harvard Medical School
will provide the ideal surroundings to support Dr. Sugden to become a successful independent scientist.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Wade William Sugden其他文献
Wade William Sugden的其他文献
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{{ truncateString('Wade William Sugden', 18)}}的其他基金
Mechanisms of Flow-driven Transcriptional Control of Hematopoietic Stem Cell Development by YAP
YAP 流驱动转录控制造血干细胞发育的机制
- 批准号:
10425468 - 财政年份:2021
- 资助金额:
$ 15.53万 - 项目类别:
Mechanisms of Flow-driven Transcriptional Control of Hematopoietic Stem Cell Development by YAP
YAP 流驱动转录控制造血干细胞发育的机制
- 批准号:
10596610 - 财政年份:2021
- 资助金额:
$ 15.53万 - 项目类别:
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