Critical Role of TBX20 in Cardiomyocyte Maturation during Direct Cardiac Reprogramming

TBX20 在直接心脏重编程过程中心肌细胞成熟中的关键作用

基本信息

批准号：
10455734
负责人：
Yang Zhou
金额：
$ 37.13万
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：
2020
资助国家：
美国
起止时间：
2020-08-25 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455734
关键词：
Affect Biological Assay Calcium Cardiac Cardiac Myocytes Cell Maturation Cells Chromatin Cicatrix Computer Analysis Data Dermal Developed Countries Development Family Fibroblasts Future Gene Activation Gene Expression Profiling Generations Genes Genetic Genetic Transcription Genomics Heart Heart failure Histones Human Image In Situ In Vitro Injury Intercellular Junctions Ion Channel Left Membrane Molecular Morbidity - disease rate Mus Myocardial Infarction Myocardial Ischemia Myofibrils Natural regeneration Neonatal Optics Patients Performance Play Process Regulation Reporting Research Residual state Role Route Sarcomeres Structure System Technology Testing Therapeutic Time Tissues Transactivation Transmission Electron Microscopy base cardiac repair clinical application clinical translation cofactor epigenomics genetic signature in vivo inducible gene expression injured insight loss of function mortality multiple omics novel overexpression penis foreskin programs protein expression single-cell RNA sequencing stem cell differentiation transcription factor transcriptome transcriptomics treatment strategy tumorigenesis voltage

项目摘要

SUMMARY Direct cardiac reprogramming to generated induced cardiomyocytes (iCMs) from fibroblasts has emerged as a promising therapeutic strategy for the treatment of heart failure, which is still the leading cause of mortality and morbidity in the developed country. While much is known regarding iCMs generated from mouse cells, the adaptation of direct cardiac reprogramming to human cells is hurdled with low efficiency and poor quality because of intrinsic differences between species. We recently reported the single cell transcriptomic analysis during human cardiac reprogramming and discovered that the insufficient generation of iCMs is associated with underdeveloped gene programs, such as ion channel and cell junction, suggesting that additional reprogramming factors regulating function of cardiomyocytes might be required. In this research program, we hypothesis that a novel reprogramming factor TBX20 plays an essential role to generate cardiomyocyte identity by establishing gene programs associated with cardiomyocyte function. In support of our hypothesis, our preliminary data have shown that TBX20 is largely under-expressed in human iCMs. While forced expression of TBX20 significantly enhanced reprogramming efficiency accompanied with activation of gene programs associated with cardiomyocyte function. To test the hypothesis, we propose to 1) further determine the impact of TBX20 on direct human cardiac reprogramming and 2) determine how TBX20 functions as an essential reprogramming factor during this process. The main objective of this proposal is to identify the critical role of TBX20 on regeneration of cardiomyocytes during direct cardiac reprogramming. The completion of this proposal will not only provide mechanistic insight into how cardiomyocyte identity can be regenerated by direct cardiac reprogramming but also enable us to generate functional-reliable cardiomyocytes directly from human non-myocytes for potential heart repair.

概括直接心脏重编程从成纤维细胞生成诱导心肌细胞（iCM）已成为一种治疗心力衰竭的有前途的治疗策略，心力衰竭仍然是死亡和死亡的主要原因发达国家的发病率。虽然人们对小鼠细胞产生的 iCM 知之甚多，但直接心脏重编程对人类细胞的适应因效率低且质量差而受到阻碍由于物种之间的内在差异。我们最近报道了单细胞转录组分析在人类心脏重编程过程中，发现 iCM 生成不足与具有不发达的基因程序，例如离子通道和细胞连接，表明额外的可能需要调节心肌细胞功能的重编程因子。在这个研究计划中，我们假设一种新的重编程因子 TBX20 在产生心肌细胞身份方面发挥重要作用通过建立与心肌细胞功能相关的基因程序。为了支持我们的假设，我们的初步数据表明，TBX20 在人类 iCM 中表达量很大程度上不足。被迫表达的同时 TBX20 显着提高重编程效率并伴随着基因程序的激活与心肌细胞功能有关。为了检验假设，我们建议 1）进一步确定影响 TBX20 对直接人类心脏重编程的影响，以及 2) 确定 TBX20 如何发挥重要作用在此过程中的重编程因子。该提案的主要目标是确定 TBX20 在直接心脏重编程过程中对心肌细胞再生的影响。本次的完成该提案不仅将提供关于如何通过直接再生心肌细胞身份的机制见解心脏重编程还使我们能够直接从人类中产生功能可靠的心肌细胞非心肌细胞用于潜在的心脏修复。