The Role of BRD4 in Cardiac Specification

BRD4 在心脏指标中的作用

• 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
• 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

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

摘要报表 心血管疾病仍然是美国的主要死亡原因。一个新兴的长期 充血性心力衰竭患者的治疗策略侧重于细胞再生。努力包括推动 现有心肌细胞的功能，将未成熟的心肌细胞引入衰竭的心脏，甚至引入 电绝缘的心肌斑块。所有这些工作都需要非常详细地了解 驱动心肌细胞谱系分化的分子决定因素及其机制基础 通过这些因子调节谱系特异性基因表达的级联反应。里程碑式的研究揭示了 BET蛋白Brd4在调节谱系特异性基因中的关键作用 通过识别或读取基因组中标有特定修饰的区域来进行编程。此外，研究还包括 在心力衰竭小鼠模型中取消BET蛋白的功能已显示出良好的结果，通过 调节特定血统的功能。然而，BET蛋白的正常作用，特别是Brd4，并不是 在心脏发育过程中被阐明。我们的数据暗示了Brd4在心脏发育过程中的关键作用， 特别是通过转录激活基因，为血统收养后的表达做好准备。我们寻求 明确Brd4在心脏发育过程中激活的确切程序。此外，我们的研究试图 了解心脏前体细胞是否容易在失去 激活信号(通过丢失Brd4)。我们的工作将为Brd4如何驱动心脏谱系提供重要的见解 规范，最终允许操作此过程以生成感兴趣的单元类型。定义 调控肌肉发生的分子途径无疑将塑造新兴的新疗法和 再生战略

项目成果

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
• 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.

• DOI: 10.1016/j.heliyon.2021.e08311
• 发表时间: 2021-11
• 期刊: Heliyon
• 影响因子: 4
• 作者: Bourque J;Opejin A;Surnov A;Iberg CA;Gross C;Jain R;Epstein JA;Hawiger D
• 通讯作者: Hawiger D