Mechanisms of outflow tract morphogenesis regulated by extracellular matrix
Mechanisms of outflow tract morphogenesis regulated by extracellular matrix
批准号:
10720451
负责人:
KIMARA L TARGOFF
金额:
$50.06万
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:
2023-06-01 至 2027-04-30
关键词:
Adrenergic AgentsAgonistArteriesBiomechanicsBiophysical ProcessBlood flowCaliberCardiacCell Differentiation processComplementComplexCongenital AbnormalityCuesDataDefectDepositionDevelopmentDimensionsDiseaseDistalDouble Outlet Right VentricleElastic FiberElasticityElastinElastin FiberElementsEmbryoEndothelial CellsEtiologyEvolutionExhibitsExtracellular MatrixExtracellular Matrix ProteinsFBLN5 geneFeedbackFibronectinsFoundationsGene FamilyGenesGeneticGlycoproteinsGrowthHeart DiseasesHeart Valve ProsthesisHumanImpairmentIndividualInfant MortalityInfluentialsLeadLiquid substanceMediatingMedicalModelingModulusMolecularMorphogenesisOperative Surgical ProceduresPathway interactionsPatientsPiezo 1 ion channelPopulationProliferatingProteinsProtocols documentationReportingRoleSecondary toSeverity of illnessSignal TransductionSmooth Muscle MyocytesStenosisStimulusStructureTestingTetralogy of FallotTissue EngineeringTissuesTitrationsTransforming Growth Factor betaTransposition of Great Vesselscardiogenesiscell typecohortcongenital heart disorderconotruncal heart defectconstrictionfibulingain of functionimprovedin vivoinnovationinsightloss of functionmalformationmechanotransductionmigrationmortalitymutantnew therapeutic targetnovelnovel therapeuticspediatric patientsprotein functionshear stress
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Congenital heart disease (CHD) is the most common birth defect in humans and patients with conotruncal
defects comprise 30% of this population. Malformations of the distal aspect of the ventricle, the infundibulum,
and the proximal aspect of the great arteries lead to conotruncal anomalies. Specific examples include
transposition of the great vessels, double outlet right ventricle, and Tetralogy of Fallot. Among this patient cohort,
the mortality rate of 17% indicates a dire need for improvement in our understanding of the early developmental
signals guiding these aberrations in outflow tract (OFT) morphogenesis. The purpose of this application is to
uncover the molecular, cellular, and biomechanical mechanisms that account for disruptions in OFT development
and underlie human conotruncal CHDs. The emerging focus on extracellular matrix (ECM) in cardiac
development and disease points to this specialized, non-cellular protein network as a key player in sculpting the
conotruncus. Yet, we have limited appreciation of the individual ECM complements functioning during OFT
formation. We identified Fibulin (Fbln) proteins as novel regulators of the ECM essential for OFT growth and
expansion. Our preliminary data demonstrate that Fblns are required to establish the proper size of the OFT.
Fblns are required for accumulation of endothelial cells (ECs) through Smad3-dependent TGF-β cues. Further,
Fblns stimulate smooth muscle cell (SMC) differentiation and elastin assembly to establish the OFT caliber.
Importantly, tissue stiffness of this auxiliary chamber is elevated; this decreased elasticity contributes to altered
flow profiles. Altogether, our preliminary data highlight that the underlying mechanisms responsible for the
impaired OFT growth in the fbln loss-of-function model are multifactorial, representing a complex interplay of
defects in EC accumulation, SMC differentiation, tissue stiffness, and flow-related factors. We put forth the
overarching hypothesis that Fbln genes are essential to establish OFT dimensions and compliance by regulating
TGF-β signals in ECs and by promoting ECM deposition by SMCs, ultimately generating shear forces that
propagate further expansion. We will examine this model with the following aims: dissect the mechanisms
mediated by fbln2 in EC accumulation and OFT growth (Aim 1), investigate the function of Fbln5 in regulating
elastin assembly, stiffness, and OFT expansion (Aim 2), and determine shear stress and mechanobiological
mechanisms operating downstream of Fbln proteins via Piezo1 in ECs and SMCs (Aim 3). Insights gained from
these proposed studies will shed light on the biomechanical mechanisms responsible for compliance and elastic
deformation at the arterial pole with implications for diseases involving stenosis of the conotruncal region.
Furthermore, probing the cell type-specific functions of Fbln proteins will augment our ability to identify novel
therapeutic targets and protocols for tissue engineering of OFT conduits and artificial valves.
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国内基金
海外基金
Agonist-GPR119-Gs复合物的结构生物学研究
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批准号:32000851
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项目类别:青年科学基金项目
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资助金额:24.0万元
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批准年份:2020
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负责人:乔安娜
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依托单位: