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Mechanisms for cell signaling in the control of cardiomyogenesis

控制心肌发生的细胞信号传导机制

基本信息

批准号：
9317530
负责人：
Kunhua Song
金额：
$ 38.88万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9317530
关键词：
Address Adult Binding Biochemistry Bioinformatics Cardiac Cardiac Myocytes Cardiac development Cellular biology Chromatin Complement Factor B Data Development Economic Burden Embryo Embryonic Heart Epigenetic Process Fibroblasts Fibrosis Foundations Genes Genomics Goals Health Health system Heart Heart failure Histones In Vitro Laboratories Lead Mediating Modification Molecular Morbidity - disease rate Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Natural regeneration Pathologic Pathway interactions Patients Pluripotent Stem Cells Production Proteomics Recruitment Activity Regulation Research Rho-associated kinase Role Signal Pathway Signal Transduction Stem cells Testing Therapeutic Transforming Growth Factors Ventricular Remodeling base cardiac regeneration cardiogenesis cost embryonic stem cell experimental study in vivo insight mortality novel novel therapeutics repaired transcription factor

项目摘要

Project Summary/Abstract Ischemic heart disease resulting in myocardial infarction (MI) and heart failure is the leading cause of morbidity and mortality in the USA. Irreversible loss of cardiomyocytes (CMs) and excessive fibrosis governed by pro- fibrotic signaling such as transforming growth factor β (TGF-β) and Rho-associated kinase (ROCK) pathways are major factors contributing to pathological ventricular remodeling in patients post-MI. It is not known whether activation of pro-fibrotic signaling inhibits CM regeneration in adult mammalian hearts following MI. Recently, our laboratory has shown that suppression of TGF-β signaling dramatically enhances the efficiency of reprogramming fibroblasts into functional CMs, which is likely related to the fact that TGF-β signaling inhibits production of CMs from embryonic stem cell-derived embryoid bodies, and cardiac progenitor cells (CPCs) in adult hearts. However, the precise molecular mechanisms by which TGF-β signaling regulates cardiomyocyte formation or cardiomyogenesis remain elusive and are the focus of this application. We hypothesize that TGF- β signaling controls cardiomyogenesis through crosstalk with epigenetic regulators. Our preliminary studies demonstrate novel roles for TGF-β signaling in the control of physical interaction between cardiac transcription factors such as Tbx5 and epigenetic regulators such as UTX, an H3K27me3 demethylase. Further studies will define the mechanisms by which the axis of TGF-β signaling-epigenetic modifications regulates cardiomyogenesis, and the roles of the axis in the control of cardiomyogenesis in developing heart and adult hearts post-MI. In vitro, we will activate or inhibit TGF-β signaling in fibroblasts expressing cardiogenic reprogramming factors, and pluripotent stem cells. We will test the hypothesis that TGF-β signaling regulates cardiomyogenesis in a manner that the effectors of TGF-β signaling such as phosphor- Smad2/3 and cardiogenic transcription factors, such as Tbx5 compete with each other for binding and recruiting epigenetic regulators to chromatin. In embryonic hearts, we will suppress TGF-β signaling globally or in specific types of CPCs to test the hypothesis that suppression of TGF-β signaling promotes differentiation of CPCs into cardiomyocytes by regulating occupancy of the chromatin modifiers during cardiac development. In adult heats post-MI, we will suppress TGF-β signaling globally or in cardiac fibroblasts and examine reprogramming factors-mediated cardiomyogenesis. We will attempt to test the hypothesis that suppression of TGF-β signaling enhances regeneration of CMs in the heart following MI. Together, results from these in vitro and in vivo studies should provide insights into cell signaling, epigenetic regulators and cardiogenic factors controlling cardiomyogenesis, and should provide the foundation to facilitate development of novel therapeutic strategies for heart regeneration.

项目总结/文摘