Endogenous and exogenous mechanisms that promote myocardial remuscularization in post infarction LV remodeling
Endogenous and exogenous mechanisms that promote myocardial remuscularization in post infarction LV remodeling
批准号:
10302748
负责人:
Jianyi Zhang
金额:
$51.98万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-08-10 至 2022-06-30
关键词:
3-DimensionalAcute myocardial infarctionAdultAnimalsApoptoticArrhythmiaBackBiomedical EngineeringBirthBlood VesselsCCND2 geneCardiacCardiac MyocytesCell CycleCell LineCell NucleusCell TransplantationCellsCicatrixCongestive Heart FailureCuesDilatation - actionDimensionsElectric StimulationEndotheliumEngineeringEngraftmentFamily suidaeFibroblastsFunctional disorderGenerationsHeartHeart failureHumanHuman EngineeringImaging technologyInfarctionInjuryLeftLeft Ventricular RemodelingLeft ventricular structureMammalsMeasurementMolecularMolecular BiologyMusMuscle CellsMyocardialMyocardial tissueMyocardiumNatural regenerationNeonatalOpticsPatientsPeriodicityPilot ProjectsProliferatingProtocols documentationPublic HealthRNARecoveryRegimenRegulatory PathwayReportingRodent ModelSignal PathwaySiteSmooth MuscleStretchingSurfaceTechniquesTechnologyTestingThickTissue EngineeringTissuesTransplantationVascularizationVentricularVentricular Arrhythmiabasecardiac tissue engineeringcell typeclinically relevanteffectiveness evaluationendothelial stem cellfunctional improvementheart functionimprovedin vivoinduced pluripotent stem cellinjuredmature animalmolecular imagingmyocardial injurynoveloverexpressionporcine modelpostnatalpreventpromoterregeneration potentialrepairedrestorationsuccesstranscriptome sequencing
中文摘要
术后促进心肌肌化的内源性和外源性机制
梗死后左室重构
总结/摘要
进行性心力衰竭的分子和细胞基础是受损的心肌细胞不能正常工作的结果。
和凋亡的心肌细胞被替换。虽然一些基于细胞和组织的疗法可以限制这一点,
功能障碍,在施用后在施用部位存活超过几周的细胞的比例
移植率极低。因此,梗死区域的实质性肌肉再生很少
报告;当报告有限的肌肉再生时,经常伴有
潜在致死性室性心律失常的机制不明。这项建议旨在恢复
通过识别细胞周期的关键调节因子,
心肌细胞(CM)重新进入细胞周期,并从“外”通过移植生物工程心肌
贴片(hCMP)与CM细胞周期上调的关键调节因子,并与之结合功能性
血管网络,并概括了一些关键的微环境线索的天然心脏组织。我们
最近建立了一种新的hiPSC细胞系,其具有MHC驱动的CM的关键调节因子CCND 2的过表达
(hiPSC-MHC-CCND 2 OE),其可以在啮齿动物模型中使受损的心室肌化。的中心目标
这一建议是为了心肌修复而将心肌细胞周期的时钟“倒转”。具体目标(SA)是:
SA 1:确定促进早期新生猪心脏细胞周期活性的关键调节因子,
心肌损伤我们将:1)使用最先进的分子生物学和成像技术,
细胞/细胞核RNA测序(scRNAseq或snRNAseq)技术,以证明这些关键
控制肌细胞细胞周期的调节因子/信号通路;以及2)测试损伤的
通过使用靶向modRNA或AAV 9操纵关键调节因子来选择性地修饰这些调节因子,
急性心肌梗死成年猪中的调节剂。SA2a。设计以前无法达到的尺寸和厚度的hCMP
其功能成熟并为体内血管化做好准备。SA2b.评估我们的
用于心肌损伤的大动物(猪)模型中的心肌恢复和肌肉重建的hCMP构建体
损伤我们将使用最先进的光学映射技术结合三维
壁内心脏标测以描绘整个左心室的潜在心律失常机制
表面和透壁。
英文摘要
Endogenous and exogenous mechanisms that promote myocardial remuscularization in post
infarction LV remodeling
Summary / Abstract
The molecular and cellular basis for the progressive heart failure is the result of the inability of damaged
and apoptotic myocytes to be replaced. While a number of cell- and tissue-based therapies can limit this
dysfunction, the proportion of cells that survive at the site of administration for more than a few weeks after
transplantation is extremely low. As such, substantial remuscularization of the infarcted region has rarely
been reported; and when limited remuscularization has been reported, it is frequently accompanied by
potentially lethal ventricular arrhythmias of unknown mechanism. This proposal aims at remuscularization of
the injured ventricle from “within” by identifying key regulators of the cell cycle and by promoting the native
cardiomyocyte (CM) reenter the cell cycle, and from “outside” by transplanting bioengineered cardiac muscle
patch (hCMP) with the key regulators of CM cell cycle upregulated, and with that incorporate a functional
vascular network and recapitulate some of the key micro environmental cues of native heart tissue. We
recently established a novel hiPSC cell line with MHC-driven overexpression of a key regulator of CM: CCND2
(hiPSC-MHC-CCND2OE), which can remuscularize injured ventricle in rodent model. The central objective of
this proposal is to “turn back the clock” of myocyte cell cycle for myocardial repair. The specific Aims ( SA) are:
SA1: Identifying the key regulators that promote cell-cycle activity in the hearts of early neonatal pigs after
myocardial injury. We will: 1) using state-of-the-art molecular biology and imaging technologies, and the single
cell/nucleus RNA sequencing (scRNAseq or snRNAseq) technology to demonstrate these key
regulators/signaling pathways that control the myocyte cell cycle; and2) test remuscularization of injured
ventricle by manipulating the key regulators using either targeted modRNA or AAV9 to selectively modify these
regulators in adult pigs with AMI. SA2a. Engineering hCMPs of previously unattainable size and thickness
that are functionally mature and primed for in-vivo vascularization. SA2b. Evaluating the effectiveness of our
hCMP constructs for myocardial recovery and remuscularization in a large-animal (swine) model of myocardial
injury. We will use state-of-the-art techniques of optical mapping in combination with the 3-dimensional
intramural cardiac mapping to delineate potential arrhythmia mechanisms over the entire left-ventricular
surface and transmurally.
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DOI:
10.1016/j.jacc.2021.09.019
发表时间:
2021-11-23
期刊:
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
影响因子:
24
作者:
[Zhang, Jianyi, Bolli, Roberto, Garry, Daniel J., Marban, Eduardo, Menasche, Philippe, Zimmermann, Wolfram-Hubertus, Kamp, Timothy J., Wu, Joseph C., Dzau, Victor J.]
通讯作者:
Dzau, Victor J.
DOI:
10.1007/978-1-4939-2572-8_8
发表时间:
2015
期刊:
Methods in molecular biology
影响因子:
--
作者:
[L. Ye;Joydeep Basu;Jianyi(Jay) Zhang]
通讯作者:
L. Ye;Joydeep Basu;Jianyi(Jay) Zhang
DOI:
10.1161/circresaha.117.311504
发表时间:
2018-01-05
期刊:
Circulation research
影响因子:
20.1
作者:
[Zhu W, Zhao M, Mattapally S, Chen S, Zhang J]
通讯作者:
Zhang J
DOI:
10.1038/s41598-023-32293-1
发表时间:
2023-04-26
期刊:
Scientific reports
影响因子:
4.6
作者:
[Nguyen T, Wei Y, Nakada Y, Chen JY, Zhou Y, Walcott G, Zhang J]
通讯作者:
Zhang J
DOI:
10.1161/circresaha.117.311819
发表时间:
2017-11-10
期刊:
Circulation research
影响因子:
20.1
作者:
[Yang L, Gao L, Nickel T, Yang J, Zhou J, Gilbertsen A, Geng Z, Johnson C, Young B, Henke C, Gourley GR, Zhang J]
通讯作者:
Zhang J
共 27 条
Project 1 - Endogenous and Exogenous Mechanisms that Promote Myocardial Remuscularization
-
批准号:10677730
-
项目类别:
-
资助金额:$55.33万
-
财政年份:2022
-
负责人:Jianyi Zhang
-
依托单位:
Core A: Administrative Core
-
批准号:10493835
-
项目类别:
-
资助金额:$39.8万
-
财政年份:2022
-
负责人:Jianyi Zhang
-
依托单位:
Project 1 - Endogenous and Exogenous Mechanisms that Promote Myocardial Remuscularization
-
批准号:10493838
-
项目类别:
-
资助金额:$39.8万
-
财政年份:2022
-
负责人:Jianyi Zhang
-
依托单位:
Mechanisms that Govern Cardiomyocyte Proliferation and Remuscularization following Ventricular Injury
-
批准号:10677719
-
项目类别:
-
资助金额:$232.73万
-
财政年份:2022
-
负责人:Jianyi Zhang
-
依托单位:
Core A: Administrative Core
-
批准号:10677720
-
项目类别:
-
资助金额:$22.0万
-
财政年份:2022
-
负责人:Jianyi Zhang
-
依托单位:
Mechanisms that Govern Cardiomyocyte Proliferation and Remuscularization following Ventricular Injury
-
批准号:10493834
-
项目类别:
-
资助金额:$238.79万
-
财政年份:2022
-
负责人:Jianyi Zhang
-
依托单位:
Bioenergetics in Hypertrophied and Remodeled Left Ventricle
-
批准号:8676931
-
项目类别:
-
资助金额:$64.11万
-
财政年份:2012
-
负责人:Jianyi Zhang
-
依托单位:
Bioenergetics in Hypertrophied and Remodeled Left Ventricle
-
批准号:9162316
-
项目类别:
-
资助金额:$58.0万
-
财政年份:2012
-
负责人:Jianyi Zhang
-
依托单位:
Cell Therapy in Hypertrophied and Remodeled Left Ventricle
-
批准号:9391517
-
项目类别:
-
资助金额:$64.65万
-
财政年份:2012
-
负责人:Jianyi Zhang
-
依托单位:
Bioenergetics in Hypertrophied and Remodeled Left Ventricle
-
批准号:8528711
-
项目类别:
-
资助金额:$62.28万
-
财政年份:2012
-
负责人:Jianyi Zhang
-
依托单位:
Bioenergetics in Hypertrophied and Remodeled Left Ventricle
-
批准号:8385977
-
项目类别:
-
资助金额:$66.72万
-
财政年份:2012
-
负责人:Jianyi Zhang
-
依托单位:
Stem Cells For Myocardial Repair: A Large Bore Magnet Study
-
批准号:8277096
-
项目类别:
-
资助金额:$47.46万
-
财政年份:2009
-
负责人:Jianyi Zhang
-
依托单位:
Mycardial Repair Using Human iPSC Derived Cardiac Muscle Patch
-
批准号:9170421
-
项目类别:
-
资助金额:$47.15万
-
财政年份:2009
-
负责人:Jianyi Zhang
-
依托单位:
Stem Cells For Myocardial Repair: A Large Bore Magnet Study
-
批准号:8076911
-
项目类别:
-
资助金额:$47.85万
-
财政年份:2009
-
负责人:Jianyi Zhang
-
依托单位:
Mycardial Repair Using Human iPSC Derived Cardiac Muscle Patch
-
批准号:8998970
-
项目类别:
-
资助金额:$47.15万
-
财政年份:2009
-
负责人:Jianyi Zhang
-
依托单位:
Myocardial repair using human iPSC derived cardiac muscle patch
-
批准号:8711999
-
项目类别:
-
资助金额:$48.67万
-
财政年份:2009
-
负责人:Jianyi Zhang
-
依托单位:
Stem Cells For Myocardial Repair: A Large Bore Magnet Study
-
批准号:7876876
-
项目类别:
-
资助金额:$48.09万
-
财政年份:2009
-
负责人:Jianyi Zhang
-
依托单位:
Stem Cells For Myocardial Repair: A Large Bore Magnet Study
-
批准号:7667575
-
项目类别:
-
资助金额:$47.72万
-
财政年份:2009
-
负责人:Jianyi Zhang
-
依托单位:
Stem cell patch therapy in hearts with LV infarction
-
批准号:6761726
-
项目类别:
-
资助金额:$22.02万
-
财政年份:2002
-
负责人:Jianyi Zhang
-
依托单位:
Stem cell patch therapy in hearts with LV infarction
-
批准号:6665061
-
项目类别:
-
资助金额:$22.02万
-
财政年份:2002
-
负责人:Jianyi Zhang
-
依托单位:
海外基金