Microphysiological Model of Human Cardiac Sympathetic Innervation
人类心脏交感神经支配的微生理模型
基本信息
- 批准号:10869757
- 负责人:
- 金额:$ 7.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAddressAffectAnimal ModelAreaArrhythmiaAutonomic nervous systemBasic ScienceCardiacCardiac MyocytesCardiac OutputCardiomyopathiesCell NucleusCellsCoculture TechniquesDataDesmosomesDevelopmentDiabetes MellitusDisease ProgressionDisease modelDisparityElectrodesElectrophysiology (science)EtiologyEvaluationExhibitsFeedbackGene MutationGenesGeneticGoalsGrowthHeartHeart DiseasesHumanImpairmentIn VitroMeasuresMicroelectrodesMicrofabricationMitotic Cell CycleModelingMolecularMonitorMuscle CellsMyocardial InfarctionNatural regenerationNeonatalNerveNeuronsNeuropathyPathogenesisPathogenicityPatientsPerformancePhenotypePhysiologicalPhysiologyPopulationProcessPropertyRegulationReporterResearchResolutionRodentRoleSpecific qualifier valueStructureStructure of superior cervical ganglionSudden DeathSympathectomySystemTechniquesTestingTherapeuticTissuesTranslational ResearchVentricularVentricular ArrhythmiaWorkarrhythmogenic cardiomyopathycardiac muscle diseasechronotropiccost effectivedevelopmental diseasedisease phenotypedrug testingelectric impedancefallsheart functionheart innervationhuman diseasehuman embryonic stem cellhuman modelin vitro Modelin vivoinduced pluripotent stem cellinduced pluripotent stem cell derived cardiomyocytesinsightmicrophysiology systemmultimodalitynerve supplyneuroregulationnovelnovel therapeuticsoptogeneticspre-clinicalsynaptogenesistargeted treatmenttissue culturetranscriptometranscriptome sequencingtranscriptomics
项目摘要
PROJECT SUMMARY
Goal: We will develop and validate a microphysiological platform of human cardiac sympathetic innervation for
in vitro modeling of the human cardiac sympathetic innervation and apply autonomic neuron specification and
its interaction with a fatal cardiac disease. The heart is heavily innervated by the autonomic nervous system that
consists of both parasympathetic and sympathetic nerves, providing feedback control and regulate overall
cardiac performance. Historically, the development of new therapeutic agents targeting cardiac neuropathies
have utilized animal models, which exhibited various limitations due to the disparity in homeostatic mechanisms
of autonomic nervous systems and the inability to recapitulate accurate human disease phenotypes. In our
proposed work, we will develop a novel compartmentalized 3D microelectrode array (MEA) co-culture platform
to model human sympathetic innervation and address the fundamental questions on sympatho-cardiac
connections, reciprocal regulation, and development of cardiac and autonomic cells. Furthermore, with
arrhythmogenic cardiomyopathy (ACM) patient-derived human induced pluripotent stem cells (hiPSC), we
expect to recapitulate ACM syndromic phenotypes and examine the diseased cardiac sympathetic innervation
on our microphysiological platform, conducive to understanding neuromodulation as well as the neuronal
contribution to heart function and disease. We will leverage state-of-art techniques developed by our team: (1)
high-throughput multimodal 3D microelectrode arrays, (2) single-cell transcriptomes from human autonomic
neurons and cardiac cells for a continuum of molecular changes during their interactions, (3) genetic reporter
systems with isogenic control cells to define specific human autonomic neuron populations and perform high-
resolution analysis of the neuron-cardiac connection, (4) the optogenetic control of neuronal activities on
connected cardiac tissue. Focus/Aim: Our proposed research focuses on developing an in vitro platform to
study neuro-cardiac interactions with hiPSCs. We will develop and optimize a compartmentalized 3D MEA co-
culture platform in multi-well format to monitor electrophysiology properties of cardiomyocytes, sympathetic
neurons and neuro-cardiac junction, followed by evaluation of the platform’s ability to support functional synapse
formation with optogenetic neuronal stimulation (Aim 1). We will also generate the developmental trajectory of
hiPSC-cardiomyocytes connected to hiPSC-sympathetic neurons through single cell transcriptomic analysis, as
well as structural and functional changes in hiPSC-CMs following neuronal stimulations (Aim 2). Furthermore,
we will examine whether the innervation affects cell fate choice (Aim 2). In Aim 3, we will employ ACM patient-
derived hiPSC/hESCs harboring desmosomal gene mutations onto our microphysiological platform and
investigate the role of sympathetic innervation in pathogenic phenotypes presented by ACM, which will be
validated in vivo. The proposed in vitro model of cardiac autonomic innervation could provide broad applications,
including preclinical drug testing and in vitro disease modeling for etiological understanding of cardiac autonomic
cardiomyopathies and neuropathies.
项目总结
目的:建立并验证人体心脏交感神经支配的微生理平台。
人心脏交感神经支配的体外模拟和应用自主神经规范和
它与一种致命的心脏病相互作用。心脏受到自主神经系统的高度神经支配,
由副交感神经和交感神经组成,提供反馈控制和整体调节
心脏功能。从历史上看,针对心脏神经疾病的新治疗药物的开发
都使用了动物模型,由于体内平衡机制的差异,这些模型表现出了各种局限性
自主神经系统和无法概括准确的人类疾病表型。在我们的
提出的工作,我们将开发一种新型的分区三维微电极阵列(MEA)共培养平台
人体交感神经支配模型及交感心脏研究的基本问题
心脏和自主神经细胞的连接、相互调节和发育。此外,有了
致心律失常心肌病(ACM)患者来源的人诱导多能干细胞(HiPSC),WE
期望总结ACM综合征的表型,并检查病变的心脏交感神经支配
在我们的微生理平台上,有助于了解神经调节以及神经元
对心脏功能和疾病的贡献。我们将利用我们团队开发的最先进技术:(1)
高通量多模式三维微电极阵列,(2)人类自主神经单细胞转录本
神经元和心肌细胞在相互作用过程中分子变化的连续体,(3)遗传报告
具有同基因控制细胞的系统,以定义特定的人类自主神经元群体,并执行高
神经-心脏联系的分辨率分析,(4)神经活动的光遗传控制
相连的心脏组织。焦点/目标:我们建议的研究重点是开发一个体外平台
研究神经-心脏与HiPSCs的相互作用。我们将开发和优化划分的3D MEA co-
用于监测交感心肌细胞电生理特性的多孔培养平台
神经元和神经-心脏连接,然后评估平台支持功能性突触的能力
用光发生神经元刺激形成(目标1)。我们还将生成以下发展轨迹
HiPSC-通过单细胞转录分析连接到HiPSC交感神经元的心肌细胞,AS
以及神经元刺激后HiPSC-CMS的结构和功能变化(目标2)。此外,
我们将研究神经支配是否影响细胞命运选择(目标2)。在目标3中,我们将雇用ACM患者-
将携带桥粒基因突变的衍生的hiPSC/hESCs转移到我们的微生理平台上
研究交感神经支配在ACM致病表型中的作用
在体内进行了验证。所建立的心脏自主神经支配体外模型具有广阔的应用前景。
包括临床前药物测试和体外疾病建模,以了解心脏自主神经的病因学
心肌病和神经病。
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 }}
Deok-Ho Kim其他文献
Deok-Ho Kim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('Deok-Ho Kim', 18)}}的其他基金
High-throughput nanoIEA-based Assay for Screening Immune Cell-Vascular Interactions
用于筛选免疫细胞-血管相互作用的基于 nanoIEA 的高通量测定法
- 批准号:
10592897 - 财政年份:2023
- 资助金额:
$ 7.42万 - 项目类别:
Microphysiological Model of Human Cardiac Sympathetic Innervation
人类心脏交感神经支配的微生理模型
- 批准号:
10502626 - 财政年份:2022
- 资助金额:
$ 7.42万 - 项目类别:
Microphysiological Model of Human Cardiac Sympathetic Innervation
人类心脏交感神经支配的微生理模型
- 批准号:
10861445 - 财政年份:2022
- 资助金额:
$ 7.42万 - 项目类别:
Microphysiological Model of Human Cardiac Sympathetic Innervation
人类心脏交感神经支配的微生理模型
- 批准号:
10636892 - 财政年份:2022
- 资助金额:
$ 7.42万 - 项目类别:
A Human iPSC-based 3D Microphysiological System for Modeling Cardiac Dysfunction in Microgravity
基于人体 iPSC 的 3D 微生理系统,用于模拟微重力下的心脏功能障碍
- 批准号:
10632929 - 财政年份:2022
- 资助金额:
$ 7.42万 - 项目类别:
Transcriptomic Entropy to Quantify Maturation of PSC-Derived Cardiomyocytes
转录组熵量化 PSC 衍生心肌细胞的成熟
- 批准号:
10179233 - 财政年份:2021
- 资助金额:
$ 7.42万 - 项目类别:
Transcriptomic Entropy to Quantify Maturation of PSC-Derived Cardiomyocytes
转录组熵量化 PSC 衍生心肌细胞的成熟
- 批准号:
10378025 - 财政年份:2021
- 资助金额:
$ 7.42万 - 项目类别:
Transcriptomic Entropy to Quantify Maturation of PSC-Derived Cardiomyocytes
转录组熵量化 PSC 衍生心肌细胞的成熟
- 批准号:
10661492 - 财政年份:2021
- 资助金额:
$ 7.42万 - 项目类别:
DISEASE MODELING AND PHENOTYPIC DRUG SCREENING FOR DYSTROPHIC CARDIOMYOPATHY
营养不良性心肌病的疾病建模和表型药物筛选
- 批准号:
10164856 - 财政年份:2020
- 资助金额:
$ 7.42万 - 项目类别:
DISEASE MODELING AND PHENOTYPIC DRUG SCREENING FOR DYSTROPHIC CARDIOMYOPATHY
营养不良性心肌病的疾病建模和表型药物筛选
- 批准号:
10116566 - 财政年份:2020
- 资助金额:
$ 7.42万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 7.42万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 7.42万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 7.42万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 7.42万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 7.42万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 7.42万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 7.42万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 7.42万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 7.42万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 7.42万 - 项目类别:
Research Grant