Biomaterial Platforms to Model the Role of Mechanical Overload in MYBPC3-Linked Hypertrophic Cardiomyopathy
生物材料平台模拟机械过载在 MYBPC3 相关肥厚性心肌病中的作用
基本信息
- 批准号:10279401
- 负责人:
- 金额:$ 38.8万
- 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:2021-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:3D PrintAction PotentialsAnimal ModelAnimalsBiocompatible MaterialsBiological ModelsBlood PressureCardiacCardiac MyocytesCardiovascular DiseasesCellsClinicalDataDevelopmentDiseaseDisease ProgressionDoseElastomersEngineeringEpigenetic ProcessFailureFamilyFutureGene ExpressionGenesGeneticGenetic studyGenotypeHDAC1 geneHeartHeart DiseasesHeart HypertrophyHematological DiseaseHereditary DiseaseHeterogeneityHistone DeacetylaseHumanHydrogelsHypertensionHypertrophic CardiomyopathyHypertrophyIn SituIn VitroIndividualInduced MutationInheritedLeadLinkMagnetismMechanical StressMechanicsMedicineMitogen-Activated Protein KinasesMoldsMolecularMorphologyMutationMyocardiumOperative Surgical ProceduresPathogenesisPathologicPathologyPatientsPharmaceutical PreparationsPharmacotherapyPhenotypePhysiologicalProteinsResearch DesignResistanceRoleSarcomeresSignal TransductionStructureSudden DeathSymptomsSystemTechnologyTestingTherapeuticTimeTissue ModelTissuesbaseblood pressure reductionelastomericengineered stem cellsexperiencehuman stem cellsin vivoinduced pluripotent stem cellloss of function mutationmagnetic fieldmechanical loadmouse modelmutantmyosin-binding protein Cnon-geneticnon-invasive monitornovelnovel therapeutic interventionprogramsprophylacticresponserole modelscaffold
项目摘要
Hypertrophic Cardiomyopathy (HCM) is the most common inherited heart disease and
the most common cause of sudden death in young people. While genetic studies have
identified specific sarcomere genes associated with HCM, they fail to predict which
patients will develop HCM. This proposal is motivated by mounting clinical and animal
model evidence for mechanical epigenetic factors possibly explaining this variance.
These data suggest that mechanical overload on the heart, caused by hypertension,
can act together with sarcomere mutations to cause maladaptive hypertrophic
remodeling in HCM. We are also motivated by the need to identify the factors underlying
the failure of drug treatments to reverse HCM: although medicines that reduce blood
pressure can reverse idiopathic (non-genetic) hypertrophy, they fail to reverse the
course of symptomatic HCM. Based upon these prior data, we hypothesize that HCM
mutations alter the magnitude of cardiac overload required to induce hypertrophic
remodeling and shorten the timeframe over which remodeling is reversible.
We aim to dissect the molecular mechanisms through which mechanical loading
integrates with sarcomere mutations to cause structural and functional pathology in
HCM linked to mutations in Myosin Binding Protein C (MYBPC3). This is possible for
the first time because we have developed a medium-throughput, human induced
pluripotent stem cell (iPSC) derived micro-heart muscle model system that allows us to
apply a controlled magnitude of mechanical overload to iPSC-derived cardiomyocytes.
This system will enable us to characterize the effects of overload on micro-heart muscle
derived from both iPSC without disease mutations, and from iPSC engineered to harbor
HCM patient specific MYPBC3 mutations (Aim 1). We will extend our magnetic hydrogel
technologies to dynamically control the magnitude of mechanical overload on micro-
heart muscles in situ, enabling us to determine mechanisms through which HCM
mutations render cardiomyocytes resistant to blood pressure reducing therapeutics (Aim
2). Finally, we will determine molecular mechanisms linking mechanical overload and
MYBPC3 mutations with hypertrophic remodeling (Aim 3).
肥厚性心肌病(HCM)是最常见的遗传性心脏病,
是年轻人猝死的最常见原因虽然遗传学研究
他们确定了与HCM相关的特定肌节基因,但未能预测其中哪些基因
患者会出现HCM。该提案的动机是通过增加临床和动物
机械表观遗传因素的模型证据可能解释这种差异。
这些数据表明,由高血压引起的心脏机械负荷过重,
可与肌节突变共同作用,
HCM的重塑我们的动机还在于需要查明造成这种情况的因素,
药物治疗逆转HCM的失败:尽管减少血液循环的药物
压力可以逆转特发性(非遗传性)肥大,他们未能逆转
症状性HCM的病程。基于这些先前的数据,我们假设HCM
突变改变了诱导肥厚性心肌病所需的心脏超负荷的程度,
重塑并缩短重塑可逆的时间框架。
我们的目标是剖析分子机制,通过机械加载
与肌节突变整合,导致结构和功能病理学,
HCM与肌球蛋白结合蛋白C(MYBPC3)突变有关。都有可能出现这种情况
第一次是因为我们已经开发了一种中等通量的,人类诱导的
多能干细胞(iPSC)衍生的微型心肌模型系统,使我们能够
对iPSC衍生的心肌细胞施加受控大小的机械过载。
该系统将使我们能够表征超负荷对微型心肌的影响
来源于没有疾病突变的iPSC和工程化的iPSC
HCM患者特异性MYPBC3突变(目的1)。我们将把磁性水凝胶
动态控制微机械过载大小的技术,
心肌原位,使我们能够确定HCM的机制,
突变使心肌细胞对降压疗法产生抵抗(Aim
2)。最后,我们将确定连接机械过载和
MYBPC3突变伴肥厚性重塑(Aim 3)。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Nathaniel Huebsch其他文献
Nathaniel Huebsch的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Nathaniel Huebsch', 18)}}的其他基金
Biomaterial Platforms to Model the Role of Mechanical Overload in MYBPC3-Linked Hypertrophic Cardiomyopathy
生物材料平台模拟机械过载在 MYBPC3 相关肥厚性心肌病中的作用
- 批准号:
10470314 - 财政年份:2021
- 资助金额:
$ 38.8万 - 项目类别:
Biomaterial Platforms to Model the Role of Mechanical Overload in MYBPC3-Linked Hypertrophic Cardiomyopathy
生物材料平台模拟机械过载在 MYBPC3 相关肥厚性心肌病中的作用
- 批准号:
10687811 - 财政年份:2021
- 资助金额:
$ 38.8万 - 项目类别:
相似海外基金
Kilohertz volumetric imaging of neuronal action potentials in awake behaving mice
清醒行为小鼠神经元动作电位的千赫兹体积成像
- 批准号:
10515267 - 财政年份:2022
- 资助金额:
$ 38.8万 - 项目类别:
Signal processing in horizontal cells of the mammalian retina – coding of visual information by calcium and sodium action potentials
哺乳动物视网膜水平细胞的信号处理 â 通过钙和钠动作电位编码视觉信息
- 批准号:
422915148 - 财政年份:2019
- 资助金额:
$ 38.8万 - 项目类别:
Research Grants
CAREER: Resolving action potentials and high-density neural signals from the surface of the brain
职业:解析来自大脑表面的动作电位和高密度神经信号
- 批准号:
1752274 - 财政年份:2018
- 资助金额:
$ 38.8万 - 项目类别:
Continuing Grant
Development of Nanosheet-Based Wireless Probes for Multi-Simultaneous Monitoring of Action Potentials and Neurotransmitters
开发基于纳米片的无线探针,用于同时监测动作电位和神经递质
- 批准号:
18H03539 - 财政年份:2018
- 资助金额:
$ 38.8万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Population Imaging of Action Potentials by Novel Two-Photon Microscopes and Genetically Encoded Voltage Indicators
通过新型双光子显微镜和基因编码电压指示器对动作电位进行群体成像
- 批准号:
9588470 - 财政年份:2018
- 资助金额:
$ 38.8万 - 项目类别:
Enhanced quantitative imaging of compound action potentials in multi-fascicular peripheral nerve with fast neural Electrical Impedance Tomography enabled by 3D multi-plane softening bioelectronics
通过 3D 多平面软化生物电子学实现快速神经电阻抗断层扫描,增强多束周围神经复合动作电位的定量成像
- 批准号:
10009724 - 财政年份:2018
- 资助金额:
$ 38.8万 - 项目类别:
Enhanced quantitative imaging of compound action potentials in multi-fascicular peripheral nerve with fast neural Electrical Impedance Tomography enabled by 3D multi-plane softening bioelectronics
通过 3D 多平面软化生物电子学实现快速神经电阻抗断层扫描,增强多束周围神经复合动作电位的定量成像
- 批准号:
10467225 - 财政年份:2018
- 资助金额:
$ 38.8万 - 项目类别:
Fast high-resolution deep photoacoustic tomography of action potentials in brains
大脑动作电位的快速高分辨率深度光声断层扫描
- 批准号:
9423398 - 财政年份:2017
- 资助金额:
$ 38.8万 - 项目类别:
NeuroGrid: a scalable system for large-scale recording of action potentials from the brain surface
NeuroGrid:用于大规模记录大脑表面动作电位的可扩展系统
- 批准号:
9357409 - 财政年份:2016
- 资助金额:
$ 38.8万 - 项目类别:
Noval regulatory mechanisms of axonal action potentials
轴突动作电位的新调节机制
- 批准号:
16K07006 - 财政年份:2016
- 资助金额:
$ 38.8万 - 项目类别:
Grant-in-Aid for Scientific Research (C)