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.

促进术后心肌再肌化的内源性和外源性机制梗死左心室重构摘要/摘要进行性心力衰竭的分子和细胞基础是受损的功能丧失的结果。虽然许多基于细胞和组织的疗法可以限制这种情况。功能障碍，即给药后在给药部位存活数周以上的细胞比例因此，梗塞区域的大量肌肉重建很少见。据报道，当出现有限的再肌化时，通常会伴有机制不明的潜在致命性室性心律失常。通过识别细胞周期的关键调节因子并促进天然的心室从“内部”修复受损的心室心肌细胞（CM）通过移植生物工程心肌从“外部”重新进入细胞周期补丁（hCMP）与CM细胞周期的关键调节剂上调，并与其中包含功能血管网络并概括了天然心脏组织的一些关键微环境线索。最近建立了一种新型 hiPSC 细胞系，其 MHC 驱动的 CM 关键调节因子 CCND2 过表达（hiPSC-MHC-CCND2OE），可以使啮齿动物模型中受伤的心室重新肌肉化。该提案是为了心肌修复而“倒转心肌细胞周期”，其具体目标（SA）是： SA1：确定促进早期新生猪心脏细胞周期活动的关键调节因子我们将：1）使用最先进的分子生物学和成像技术，以及单一的方法。细胞/细胞核 RNA 测序（scRNAseq 或 snRNAseq）技术来证明这些关键控制肌细胞周期的调节器/信号通路；2) 测试受伤的肌再生成；通过使用靶向 modRNA 或 AAV9 选择性地修改这些关键调节因子来控制心室具有 AMI 的成年猪的调节器具有以前无法达到的尺寸和厚度。功能成熟并已准备好评估我们的 SA2b 的有效性。 hCMP 构建体用于大型动物（猪）心肌模型中的心肌恢复和再肌化我们将结合使用最先进的光学测绘技术和 3 维技术。壁内心脏标测可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）

Effective Metabolic Approaches for the Energy Starved Failing Heart: Bioenergetic Resiliency via Redundancy or Something Else?

DOI：
10.1161/circresaha.118.313308
发表时间：
2018-07-20
期刊：
Circulation research
影响因子：
20.1
作者：
Zhang J;Abel ED
通讯作者：
Abel ED

Functional consequences of a tissue-engineered myocardial patch for cardiac repair in a rat infarct model.

DOI：
10.1089/ten.tea.2013.0312
发表时间：
2014-02
期刊：
Tissue engineering. Part A
影响因子：
0
作者：
Jacqueline S. Wendel;L. Ye;Pengyuan Zhang;R. Tranquillo;Jianyi(Jay) Zhang
通讯作者：
Jacqueline S. Wendel;L. Ye;Pengyuan Zhang;R. Tranquillo;Jianyi(Jay) Zhang

Thymosin β4 increases the potency of transplanted mesenchymal stem cells for myocardial repair.

DOI：
10.1161/circulationaha.112.000025
发表时间：
2013-09-10
期刊：
Circulation
影响因子：
37.8
作者：
Ye L;Zhang P;Duval S;Su L;Xiong Q;Zhang J
通讯作者：
Zhang J

Lactate Promotes Synthetic Phenotype in Vascular Smooth Muscle Cells.

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

Turning back the clock: A concise viewpoint of cardiomyocyte cell cycle activation for myocardial regeneration and repair.