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Endogenous and exogenous mechanisms that promote myocardial remuscularization in post infarction LV remodeling

梗死后左室重构中促进心肌再肌化的内源性和外源性机制

基本信息

批准号：
10302748
负责人：
Jianyi Zhang
金额：
$ 51.98万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-10 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10302748
关键词：
3-Dimensional Acute myocardial infarction Adult Animals Apoptotic Arrhythmia Back Biomedical Engineering Birth Blood Vessels CCND2 gene Cardiac Cardiac Myocytes Cell Cycle Cell Line Cell Nucleus Cell Transplantation Cells Cicatrix Congestive Heart Failure Cues Dilatation - action Dimensions Electric Stimulation Endothelium Engineering Engraftment Family suidae Fibroblasts Functional disorder Generations Heart Heart failure Human Human Engineering Imaging technology Infarction Injury Left Left Ventricular Remodeling Left ventricular structure Mammals Measurement Molecular Molecular Biology Mus Muscle Cells Myocardial Myocardial tissue Myocardium Natural regeneration Neonatal Optics Patients Periodicity Pilot Projects Proliferating Protocols documentation Public Health RNA Recovery Regimen Regulatory Pathway Reporting Rodent Model Signal Pathway Site Smooth Muscle Stretching Surface Techniques Technology Testing Thick Tissue Engineering Tissues Transplantation Vascularization Ventricular Ventricular Arrhythmia base cardiac tissue engineering cell type clinically relevant effectiveness evaluation endothelial stem cell functional improvement heart function improved in vivo induced pluripotent stem cell injured mature animal molecular imaging myocardial injury novel overexpression porcine model postnatal prevent promoter regeneration potential repaired restoration success transcriptome sequencing

项目摘要

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.

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。

项目成果

期刊论文数量（42）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Fabrication of a myocardial patch with cells differentiated from human-induced pluripotent stem cells.

DOI：
10.1007/978-1-4939-2572-8_8
发表时间：
2015
期刊：
Methods in molecular biology
影响因子：
0
作者：
L. Ye;Joydeep Basu;Jianyi(Jay) Zhang
通讯作者：
L. Ye;Joydeep Basu;Jianyi(Jay) Zhang

Basic and Translational Research in Cardiac Repair and Regeneration: JACC State-of-the-Art Review.

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.

CCND2 Overexpression Enhances the Regenerative Potency of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Remuscularization of Injured Ventricle.