Modeling myosin mechanobiology towards understanding the mechanisms of hypertrophic cardiomyopathy
模拟肌球蛋白力学生物学以了解肥厚型心肌病的机制
基本信息
- 批准号:10301337
- 负责人:
- 金额:$ 16.63万
- 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:2021-08-15 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAdhesionsAdvisory CommitteesAffectAllelesAreaAutomobile DrivingAwardBiological ModelsBiomechanicsBiomedical EngineeringCRISPR/Cas technologyCardiacCardiac MyocytesCardiac MyosinsCell AdhesionCell-Cell AdhesionCellsCellular biologyClinicalClustered Regularly Interspaced Short Palindromic RepeatsComplexComputer ModelsContractsCuesDevelopmentDiseaseDisease ProgressionElementsEngineeringEnvironmentEventExtracellular MatrixFibroblastsFibrosisFluorescence Resonance Energy TransferFunctional disorderGene ExpressionGenerationsGenesGenotypeGoalsHealthHeartHeart DiseasesHeart failureHeritabilityHeterogeneityHumanHypertrophic CardiomyopathyHypertrophyITGB3 geneIn VitroInduced MutationIntegrinsIntercellular JunctionsKineticsKnowledgeLeadLinkMAP Kinase GeneMeasurementMeasuresMechanicsMediator of activation proteinMentorsMentorshipModelingMolecularMolecular BiologyMutationMyofibrilsMyofibroblastMyosin ATPaseMyosin Heavy ChainsOrganPathologicPathway interactionsPatientsPharmacotherapyPhasePhenotypePoint MutationPositioning AttributeProductionProteinsRegulationResearchResearch SupportResearch TrainingRoleSarcomeresSeverity of illnessSignal PathwaySignal TransductionSystemTechnical ExpertiseTechniquesTestingTherapeuticTissuesTraction Force MicroscopyTrainingUniversitiesValidationVariantVinculinbeta-Myosincareercareer developmentdisease phenotypedisease-causing mutationexperienceextracellularimprovedin silicoin vivoindividualized medicineinduced pluripotent stem cellinnovationinsightmolecular phenotypemutantnew therapeutic targetnovelresearch and developmentresponsesensorsingle moleculeskill acquisitionskillsspecies differencetooltranscriptometranscriptome sequencingtranscriptomics
项目摘要
PROJECT SUMMARY: This proposed project focuses on understanding how mutations in beta cardiac myosin
with diverse and often opposing effects on myosin molecular function contribute to similar disease phenotypes
of hypertrophic cardiomyopathy (HCM): cardiomyocyte (CM) hypertrophy, hypercontractility, and tissue fibrosis.
Understanding disease mechanisms and the heterogeneity of phenotypes across multiple scales
(molecular, cellular, and clinical) will enable the development of better and more individualized therapies
for patients with HCM. The first aim of this proposal will clarify the mechanisms by which altered intracellular
forces affect intracellular signaling and CM hypertrophy. The second aim will use computational modeling to
examine how alterations to interrelated parameters of myosin function change force production temporally and
spatially. The third aim will define how altered extracellular mechanics affect CM and cardiac fibroblast
phenotypes. The proposal uses several innovative molecular, cellular, bioengineering, and computational
modeling tools to examine and contextualize the role of altered cellular mechanics in driving changes in cardiac
cell phenotypes. CRISPR/Cas9 gene editing in human induced pluripotent stem cells provides a model system
to investigate the effects of specific mutations in a dynamic cellular context. Micropatterned engineered platforms
will be used to improve myofibril alignment and allow direct measurement of intracellular force production by
traction force microscopy. Molecular biology and transcriptomic techniques will be used to measure changes in
intracellular signaling and gene expression in response to mechanical perturbation. Another innovation is the
novel application of a vinculin tension sensor FRET probe to directly measure intracellular forces at sarcomere
Z disks and at cellular adhesions. Together these platforms will allow direct validation of temporal and spatial
cellular forces predicted using computational modeling (molecular myosin models and cell-specific finite element
models). Finally, investigating the effect of altered extracellular mechanics on CM function and cardiac fibroblast
activation in engineered environments will give insights into the effects of fibrotic remodeling. The research and
career development training plans will enable the transition of Dr. Vander Roest to an independent
career. During the mentored (K99 phase) of this proposal, Dr. Vander Roest will develop technical skills in
molecular biomechanics, FRET measurements, and transcriptome analysis, and expand her skills in
computational modeling in the context of cardiac disease. This training will take place at Stanford University,
under the mentorship of Drs. Bernstein and Spudich, as well as an expert trans-disciplinary advisory committee,
including 2 experts in computational modeling (Drs. Regnier and Campbell). The development of these skills will
support the research plan for the independent phase of this project, combining new skills and experience gained
during this award with Dr. Vander Roest’s past experience in myofibroblast mechanobiology to facilitate a
successful transition to independence.
项目概述:这个项目的重点是了解β心肌肌球蛋白的突变如何
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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Alison Schroer Vander Roest其他文献
Alison Schroer Vander Roest的其他文献
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{{ truncateString('Alison Schroer Vander Roest', 18)}}的其他基金
Modeling myosin mechanobiology towards understanding the mechanisms of hypertrophic cardiomyopathy
模拟肌球蛋白力学生物学以了解肥厚型心肌病的机制
- 批准号:
10906499 - 财政年份:2023
- 资助金额:
$ 16.63万 - 项目类别:
Modeling myosin mechanobiology towards understanding the mechanisms of hypertrophic cardiomyopathy
模拟肌球蛋白力学生物学以了解肥厚型心肌病的机制
- 批准号:
10747039 - 财政年份:2023
- 资助金额:
$ 16.63万 - 项目类别:
Modeling myosin mechanobiology towards understanding the mechanisms of hypertrophic cardiomyopathy
模拟肌球蛋白力学生物学以了解肥厚型心肌病的机制
- 批准号:
10470295 - 财政年份:2021
- 资助金额:
$ 16.63万 - 项目类别:
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