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Elucidating the Molecular Mechanisms of Jun/Fos Transcription Factor Function in Cardiac Regeneration and Protection

阐明 Jun/Fos 转录因子在心脏再生和保护中功能的分子机制

基本信息

批准号：
9760024
负责人：
Arica Beisaw
金额：
$ 5.53万
依托单位：
MAX PLANCK INSTITUTE FOR HEART AND LUNG RESEARCH
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：
2020-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9760024
关键词：
ATAC-seq Acute myocardial infarction Address Adult Alleles Area Binding Biological Models Cardiac Cardiac Myocytes Cause of Death Cell Cycle Cell Death Cell Survival Cells ChIP-seq Chromatin Cicatrix Co-Immunoprecipitations Coupled Data Developed Countries Dominant-Negative Mutation Drops Embryonic Development Enzymes Epigenetic Process Epitopes Extracellular Matrix Proteins Failure Family member Genetic Genetic Models Goals Heart Heart Injuries Human Immune Inflammation Injury Innate Immune Response Ischemia JUN gene Knowledge Link Mass Spectrum Analysis Mediating MicroRNAs Modeling Molecular Mus Myocardial Myocardial Infarction Myocardial Ischemia Natural regeneration Neonatal Pathway interactions Play Process Proliferating Proteins Rattus Reporting Resolution Rodent Role Sarcomeres Signal Pathway Social Impacts Structure Testing Tissues Transgenic Mice Up-Regulation Ventricular Zebrafish base cardiac regeneration cardioprotection economic impact experimental study functional outcomes heart function improved injured insight jun Oncogene macrophage mouse model neutrophil novel overexpression postnatal preconditioning recruit regenerative repaired response therapy development transcription factor

项目摘要

Project Summary Acute myocardial infarction, and subsequent failure of the mammalian heart to restore lost cardiac tissue, is one of the leading causes of death worldwide. There is an urgent need to develop therapies that facilitate survival or regeneration of healthy heart tissue after ischemia, which would have an enormous social and economic impact worldwide. The zebrafish (Danio rerio) possesses the robust ability to regenerate functional cardiac tissue after multiple types of ventricular injury, including induction of cardiac cell death by cryoinjury. Significant progress has been made in understanding the process of heart regeneration in zebrafish. For example, following cardiac injury, remaining cardiomyocytes are thought to dedifferentiate, disassemble sarcomeric structures, and proliferate to replenish lost cardiomyocytes. However, it remains unclear how these remaining cardiomyocytes sense and respond to injury, including how transcription factor regulatory networks function to elicit sarcomere disassembly and cardiomyocyte dedifferentiation. The goal of this proposal is to investigate the transcription factor regulatory networks that function to promote heart regeneration in zebrafish. Transcription factors are known to regulate the chromatin landscape based on their ability to bind and recruit chromatin-modifying enzymes to target loci. Significant changes on the level of chromatin must likely take place in order for adult cardiomyocytes to respond to injury and elicit a regeneration response. My preliminary data indicate that Jun/Fos transcription factors respond to cardiac injury and orchestrate downstream changes in the cardiomyocyte chromatin landscape to promote cardiac regeneration. The experiments proposed here aim to further understand the link between the innate immune response to cardiac injury and activation of jun/fos expression in cardiomyocytes. Furthermore, I aim to determine the molecular mechanisms of Jun/Fos action during zebrafish heart regeneration through elucidation of direct downstream target loci and protein interaction partners that mediate changes in chromatin accessibility. Lastly, I will determine whether JUN/FOS transcription factors also play a similar role during cardioprotection and whether overexpression of Jun/Fos can stimulate regeneration in an adult mouse model. The results of the studies proposed here will provide deeper mechanistic insight into the genetic and epigenetic regulatory networks that function to promote heart regeneration. Understanding these molecular mechanisms has practical implications for guiding the development of therapies to promote regeneration in the adult mammalian heart following myocardial injury.

项目总结