From proteins to cells to tissues: A multi-scale assessment of biomechanical regulation by the myosin molecular motor
从蛋白质到细胞再到组织:肌球蛋白分子马达生物力学调节的多尺度评估
基本信息
- 批准号:10584005
- 负责人:
- 金额:$ 8.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-05-15 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:ATP HydrolysisATP phosphohydrolaseActinsAddressAffectAnimal ModelBiologicalBiological AssayBiological ModelsBiologyBiomechanicsBiophysical ProcessBiophysicsCardiac MyocytesCardiac MyosinsCell fusionCell physiologyCellsCellular StructuresClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsComplementComputer ModelsDataDevelopmentDiseaseEmbryonic DevelopmentEngineeringFutureGene ExpressionGenerationsGoalsGrowthHeartHereditary DiseaseHomeostasisHumanHuman EngineeringIndividualKineticsKnowledgeLeadLengthLinkMaintenanceMeasurementMechanicsMethodsMicrofilamentsMissionModelingMolecularMolecular MotorsMolecular TargetMotorMuscleMuscle CellsMuscle DevelopmentMuscle FibersMuscle functionMutationMyocardiumMyofibrilsMyosin ATPaseMyosin Heavy ChainsNational Institute of General Medical SciencesOrganOrganellesPerformancePhenotypePhysiologicalPilot ProjectsPoint MutationPositioning AttributeProductionPropertyProteinsProtocols documentationRecombinantsRegulationResearchResearch PersonnelSarcomeresShapesSignal PathwaySignal TransductionSkeletal MuscleSkinStructureSubgroupSumTechniquesTestingThick FilamentTissue constructsTissuesTranslatingWorkWorking strokebiomechanical testbody systemcell motilitydisease phenotypedisease-causing mutationexperimental studyhigh throughput screeninghuman diseaseinduced pluripotent stem cellinnovationinsightlensmechanical forcemechanical propertiesmultidisciplinarynew therapeutic targetoptical trapsprogramsprotein structureprotein structure functionprototypesensorsingle moleculeskeletalskeletal stem cellstem cell modelsuccesstranscriptome sequencing
项目摘要
PROJECT SUMMARY/ABSTRACT
The overarching goal of this project is to use myosin as a model system in which to address the fundamental
biological question of how alterations in tissue organization and function can arise from often subtle changes in
function at the molecular level. Force generation by myosin is required not only for the physiological functions of
skeletal muscle and the heart, but also for the proper development and maintenance of these tissues during
embryogenesis and beyond. Our team aims to develop a detailed mechanistic understanding of how force
generation by myosin acts to regulate muscle tissue development and homeostasis. We examine this general
question through the lens of asking how seemingly small changes in the activity of individual myosin molecules
can drive dramatic changes in tissue-level organization and function, for example in the context of inherited
disease. In Aim 1, we will determine how structural changes in myosin affect the chemo-mechanical properties
of the myosin-actin interaction for individual and small assemblies of motor proteins. This aim will leverage
innovative techniques developed by our team to quantify biomechanical changes induced by myosin mutations
at the single molecule level and the corresponding consequences for sarcomere-level structure and function. In
Aims 2 and 3, we will determine how changes in myosin kinetics and force production influence the growth,
maturation, and function of cells and tissues, using cardiomyocytes and skeletal myocytes as model systems.
These aims will leverage CRISPR-editing to introduce myosin mutations in isogenic hiPSC-derived cardiac and
skeletal myocytes. We will then be able to compare biomechanical alterations at the individual molecule level
with those in sub-cellular organelles (myofibrils), cells and micro-tissues. We expect to answer basic mechanistic
questions as to how alterations in protein structure and function affect cell and tissue function, changing force
and plasticity, and provide a window into understanding how cells adapt to alterations in changing mechanical
forces. We will then be positioned to utilize our hiPSC platforms for high-throughput screens to develop novel
therapies targeted to phenotypic subgroups of myosin mutations. Another major goal of our Research Program
is to support Early Stage Investigators (ESI). We will support pilot studies from ESI investigators that explore
innovative research questions relevant to our Research Program. Critical to the NIGMS mission, our team’s
multi-disciplinary integrated approach, spanning the scale from individual molecules to sub-cellular structures to
whole cells to engineered micro-tissues, will serve as a prototype for teams undertaking future studies using
hiPSCs to explore other biological protein assemblies, using human disease-producing mutations as
perturbations to define their molecular and functional mechanisms across organ systems.
项目概要/摘要
该项目的总体目标是使用肌球蛋白作为模型系统来解决基本问题
组织组织和功能的改变如何由经常微妙的变化引起的生物学问题
肌球蛋白产生的力不仅是生理功能所必需的。
骨骼肌和心脏,也为了这些组织的适当发育和维护
我们的团队旨在对力如何产生详细的机制理解。
肌球蛋白的产生可调节肌肉组织的发育和体内平衡。
通过询问单个肌球蛋白分子的活性看似微小的变化是如何产生的
可以推动组织水平的组织和功能发生巨大变化,例如在遗传方面
在目标 1 中,我们将确定肌球蛋白的结构变化如何影响化学机械特性。
单个和小运动蛋白组装体的肌球蛋白-肌动蛋白相互作用的研究将利用这一目标。
我们团队开发的创新技术用于量化肌球蛋白突变引起的生物力学变化
在单分子水平上以及对肌节水平结构和功能的相应影响。
目标 2 和 3,我们将确定肌球蛋白动力学和力量产生的变化如何影响生长,
使用心肌细胞和骨骼肌细胞作为模型系统,研究细胞和组织的成熟和功能。
这些目标将利用 CRISPR 编辑在同基因 hiPSC 衍生的心脏和
然后我们将能够在单个分子水平上比较生物力学的变化。
我们期望回答基本的机制。
关于蛋白质结构和功能的改变如何影响细胞和组织功能、改变力的问题
和可塑性,并为了解细胞如何适应不断变化的机械变化提供了一个窗口
然后,我们将利用我们的 hiPSC 平台进行高通量筛选来开发新颖的药物。
针对肌球蛋白突变表型亚组的疗法是我们研究计划的另一个主要目标。
是为了支持早期研究者 (ESI) 我们将支持 ESI 研究者探索的试点研究。
与我们的研究计划相关的创新研究问题对于我们团队的 NIGMS 使命至关重要。
多学科综合方法,涵盖从单个分子到亚细胞结构到
从整个细胞到工程微组织,将作为团队进行未来研究的原型
hiPSC 探索其他生物蛋白质组装体,利用人类疾病产生的突变作为
扰动来定义其跨器官系统的分子和功能机制。
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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Daniel Bernstein其他文献
Daniel Bernstein的其他文献
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{{ truncateString('Daniel Bernstein', 18)}}的其他基金
RE-ENERGIZE FONTAN - RandomizEd Exercise INtERvention desiGned to MaximIZE Fitness in Pediatric FONTAN patients
重新激活 FONTAN - 随机运动干预旨在最大限度地提高儿童 FONTAN 患者的健康状况
- 批准号:
9893292 - 财政年份:2020
- 资助金额:
$ 8.49万 - 项目类别:
RE-ENERGIZE FONTAN - RandomizEd Exercise INtERvention desiGned to MaximIZE Fitness in Pediatric FONTAN patients
重新激活 FONTAN - 随机运动干预旨在最大限度地提高儿童 FONTAN 患者的健康状况
- 批准号:
10274780 - 财政年份:2020
- 资助金额:
$ 8.49万 - 项目类别:
RE-ENERGIZE FONTAN - RandomizEd Exercise INtERvention desiGned to MaximIZE Fitness in Pediatric FONTAN patients
重新激活 FONTAN - 随机运动干预旨在最大限度地提高儿童 FONTAN 患者的健康状况
- 批准号:
10589103 - 财政年份:2020
- 资助金额:
$ 8.49万 - 项目类别:
RE-ENERGIZE FONTAN - RandomizEd Exercise INtERvention desiGned to MaximIZE Fitness in Pediatric FONTAN patients
重新激活 FONTAN - 随机运动干预旨在最大限度地提高儿童 FONTAN 患者的健康状况
- 批准号:
10378166 - 财政年份:2020
- 资助金额:
$ 8.49万 - 项目类别:
From proteins to cells to tissues: A multi-scale assessment of biomechanical regulation by the myosin molecular motor
从蛋白质到细胞再到组织:肌球蛋白分子马达生物力学调节的多尺度评估
- 批准号:
10615077 - 财政年份:2019
- 资助金额:
$ 8.49万 - 项目类别:
From proteins to cells to tissues: A multi-scale assessment of biomechanical regulation by the myosin molecular motor
从蛋白质到细胞再到组织:肌球蛋白分子马达生物力学调节的多尺度评估
- 批准号:
10396504 - 财政年份:2019
- 资助金额:
$ 8.49万 - 项目类别:
From proteins to cells to tissues: A multi-scale assessment of biomechanical regulation by the myosin molecular motor
从蛋白质到细胞再到组织:肌球蛋白分子马达生物力学调节的多尺度评估
- 批准号:
10291393 - 财政年份:2019
- 资助金额:
$ 8.49万 - 项目类别:
hiPSC-Cardiomyocytes to Screen Variants Predictive of Doxorubicin Cardiotoxicity
hiPSC-心肌细胞筛选预测阿霉素心脏毒性的变异体
- 批准号:
8909180 - 财政年份:2014
- 资助金额:
$ 8.49万 - 项目类别:
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