The Role of BRD4 in Cardiac Specification

BRD4 在心脏指标中的作用

基本信息

批准号：
10394203
负责人：
Rajan Jain
金额：
$ 40.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394203
关键词：
Adopted Adoption Area Binding Bromodomain Cardiac Cardiac Myocytes Cardiac development Cardiovascular Diseases Cause of Death Cell Differentiation process Cell Therapy Cells ChIP-seq Chemicals Complex Congestive Heart Failure Cues Data Development Embryo Endothelium Family member Flow Cytometry Foundations Gene Activation Gene Expression Genes Genetic Genetic Transcription Genome Goals Heart Heart failure Histones Human Immunohistochemistry In Vitro Laboratories Lysine Modeling Modification Molecular Mus Muscle Cells Myocardium Nucleic Acid Regulatory Sequences Pathway interactions Patients Pregnancy Process Proteins Reader Reading Regulator Genes Regulatory Element Repression Role Series Shapes Smooth Muscle Myocytes Tertiary Protein Structure Testing Tissues United States Work cardiogenesis cell regeneration cell type embryonic stem cell experimental study fetal field study in vivo insight interest mouse model mutant myogenesis novel therapeutics progenitor programs protein function regenerative regenerative approach regenerative therapy stem cells tumor progression

项目摘要

Summary Statement Cardiovascular disease remains the leading cause of death in the United States. One emerging long-term strategy for patients with congestive heart failure focuses on cellular regeneration. Efforts include boosting the function of existing cardiac myocytes, introducing immature myocytes into failing hearts, and even introducing electrically insulated patches of myocardium. All of these efforts require a highly-detailed understanding of the molecular determinants that drive myocyte lineage specification and differentiation and the mechanistic basis by which these factors regulate lineage specific gene expression cascades. Landmark studies have revealed a critical role for the Bromodomain extraterminal domain (BET) protein Brd4 in regulating lineage specific gene programs by recognizing or reading areas of the genome marked by specific modifications. In addition, studies abrogating BET protein function in murine models of heart failure have demonstrated promising results, by modulating lineage specific function. However, the normal role of BET proteins, specifically Brd4, has not been elucidated during cardiac development. Our data implicates a critical role for Brd4 during cardiac development, specifically by transcriptionally activating genes poised for expression upon lineage adoption. We seek to define the exact programs activated by Brd4 during cardiac development. In addition, our studies seek to understand if cardiac progenitor cells are rendered vulnerable to adopting aberrant cell fates upon loss of activation cues (via loss of Brd4). Our work will provide essential insight into how Brd4 drives cardiac lineage specification, ultimately allowing for manipulation of this process to generate cell types of interest. Defining the molecular pathways which regulate myogenesis will undoubtedly shape emerging novel therapeutics and regenerative strategi

摘要声明心血管疾病仍然是美国死亡的主要原因。长期出现的一项充血性心力衰竭患者的策略集中在细胞再生上。努力包括提高现有心肌细胞的功能，将未成熟的心肌细胞引入失败的心脏，甚至引入心肌的电绝缘斑块。所有这些努力都需要对驱动心肌谱系规范和分化以及机械基础的分子决定因素这些因素调节特定基因表达级联。地标研究表明溴结构域外部元素（BET）蛋白BRD4在调节谱系特定基因中的关键作用通过以特定修改为标志的基因组的程序或阅读区域。另外，研究在心力衰竭的鼠模型中，废除BET蛋白功能已证明了有希望的结果调节谱系特定功能。但是，BET蛋白（特别是BRD4）的正常作用尚未是在心脏发展过程中阐明。我们的数据暗示BRD4在心脏发展过程中的关键作用，特别是通过转录激活基因在谱系采用后表达的基因。我们寻求定义心脏发育过程中BRD4激活的确切程序。此外，我们的研究试图了解心脏祖细胞是否容易在损失后容易采用异常细胞的命运激活提示（通过BRD4的丢失）。我们的工作将提供有关BRD4如何驱动心脏血统的基本见解规范，最终允许操纵此过程以产生感兴趣的细胞类型。定义调节肌发生的分子途径无疑会塑造新的新型治疗剂和再生策略

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure Pathogenesis.

染色质重塑驱动心力衰竭发病机制中的免疫成纤维细胞串扰。

DOI：
10.1101/2023.01.06.522937
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Alexanian,Michael;Padmanabhan,Arun;Nishino,Tomohiro;Travers,JoshuaG;Ye,Lin;Lee,ClaraYoungna;Sadagopan,Nandhini;Huang,Yu;Pelonero,Angelo;Auclair,Kirsten;Zhu,Ada;Teran,BarbaraGonzalez;Flanigan,Will;Kim,CharisKee-Seon;Lumbao-C
通讯作者：
Lumbao-C

Landscape of Hopx expression in cells of the immune system.