Hemodynamic Contributions to Vascular Dysfunction in Pulmonary Arterial Hypertension
Hemodynamic Contributions to Vascular Dysfunction in Pulmonary Arterial Hypertension
批准号:
10570134
负责人:
Samuel Gibson Rayner
金额:
$18.67万
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:
2023-04-15 至 2028-03-31
关键词:
Abnormal CellAddressAffectBasic ScienceBehaviorBioinformaticsBiomedical EngineeringBlood VesselsBlood flowCalcium SignalingCellsCellular biologyCessation of lifeCollagenCommunicationComplexCoupledCuesDataDevelopmentDevelopment PlansDiagnosisDiseaseEndothelial CellsEngineeringEnvironmental Risk FactorExposure toFunctional disorderFutureGene Expression ProfileGenetic TranscriptionGoalsHumanImmunofluorescence ImmunologicIndividualInvestigationLaboratoriesLungMentorshipMethodsMicrofluidic MicrochipsMicrofluidicsModelingModernizationMorphologyPathogenesisPathologicPathway interactionsPatientsPatternPersonsPharmacologic SubstancePhenotypePhysiciansPhysiologicalPlayPositioning AttributeProductionProliferatingPulmonary Vascular ResistancePulmonary artery structureResearchResearch ProposalsRoleScientistSignal PathwaySignal TransductionSmooth Muscle MyocytesTechniquesTherapeuticTherapeutic InterventionTimeTrainingTranslational ResearchVascular DiseasesVascular remodelingWorkarteriolecareer developmentcombinatorialdesignhemodynamicsnew therapeutic targetnext generation sequencingnovelprecision medicinepressurepreventprogramsprototypepulmonary arterial hypertensionpulmonary artery endothelial cellpulmonary vascular cellsresponseright ventricular failurescreeningshear stresssingle-cell RNA sequencingskillssuccesstranscriptome sequencingtranscriptomics
中文摘要
项目总结/文摘
英文摘要
Project Summary/Abstract
Pulmonary arterial hypertension (PAH) is a progressive and ultimately fatal disease with a median survival
from diagnosis of approximately six years despite modern treatments. Up to 1 in 20,000 people are affected,
and no available therapies cure or prevent this disease. PAH is characterized by pulmonary arterial endothelial
cell (PAEC) and smooth muscle cell (PASMC) dysfunction leading to increased pulmonary vascular resistance
and death from right heart failure. Abnormal hemodynamic forces are the primary cause of PAH in some
patients, and in all cases may contribute to progression. The small pulmonary arteries in PAH are exposed to
both increases in shear stress and pressure forces. Increased shear stress has previously been shown to
cause EC changes mimicking those seen in PAH. Dr. Rayner has obtained preliminary data showing that
PAECs from subjects with PAH have divergent transcriptomic responses to pathologically high shear stress
when compared with controls. This suggests that patient abnormalities in shear-sensitive pathways may be a
potential unifying mechanism in PAH that could provide targets for future therapeutics.
Dr. Rayner’s overall goal is to define how shear and pressure forces combine with underlying patient factors to
drive vascular dysfunction and promote PAH. Dr. Rayner has a research program focused on applying novel
bioengineering techniques to the study of PAH. His research proposal will use a resistor-coupled microfluidic
device to allow pressure and shear forces to be evaluated both individually and in combination. Dr. Rayner has
also developed a novel pulmonary arteriole-on-a-chip (AOC) model that will be employed in this proposal to
evaluate EC-SMC signaling and coordinated vascular behavior. Dr. Rayner’s research goal will be
accomplished through three aims: 1) Evaluate the effects of shear and pressure on control and PAH PAECs in
a resistor-coupled microfluidic platform; 2) Determine how pressure and patient factors influence cell
phenotypes in PASMC-only AOCs; 3) Identify the effect of hemodynamic and patient factors on cell
phenotypes and PAEC to PASMC signaling within patient-specific multicellular AOC models.
These specific aims are well-aligned to the main training aims of Dr. Rayner’s Career Development Plan, which
are to gain essential additional training in pulmonary vascular cell biology, bioinformatics, and vascular
engineering. Dr. Rayner will gain these skills through a combination of formal didactics, experiential training,
and close mentorship by a world-class team of scientists with relevant expertise. These new skills will augment
his background in bioengineering and translational PAH research and facilitate his overall goal of developing
into an independent physician-scientist doing basic and translational research on PAH. With his own unique
engineered vascular platforms and the data generated through this research, Dr. Rayner will be well-positioned
to submit a competitive R01 proposal near the end of his proposed K08 research period.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Modeling Von Willebrand Factor Behavior in the Pulmonary Circulation in Health and Disease
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批准号:9789035
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项目类别:
-
资助金额:$3.79万
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财政年份:2018
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负责人:Samuel Gibson Rayner
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依托单位:
海外基金