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

简要说明 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。努力包括促进 现有的心肌细胞的功能，将未成熟的心肌细胞引入衰竭的心脏，甚至引入 电绝缘的心肌补片。所有这些努力都需要对 驱动肌细胞谱系特化和分化的分子决定因素及其机制基础 这些因子通过其调节谱系特异性基因表达级联。具有里程碑意义的研究表明， 溴结构域末端外结构域（BET）蛋白Brd4在调节谱系特异性基因中的关键作用 通过识别或阅读基因组中被特定修饰标记的区域来编程。另外研究 在心力衰竭的鼠模型中消除BET蛋白功能已经证明了有希望的结果， 调节谱系特异性功能。然而，BET蛋白，特别是Brd4的正常作用尚未被证实。 在心脏发育过程中阐明。我们的数据暗示Brd4在心脏发育过程中的关键作用， 特别是通过转录激活准备在谱系采用时表达的基因。我们寻求 定义心脏发育过程中Brd4激活的确切程序。此外，我们的研究旨在 了解心脏祖细胞是否容易在丧失功能后接受异常细胞命运。 激活线索（通过Brd4的丢失）。我们的工作将为Brd4如何驱动心脏谱系提供重要的见解 本发明提供了一种细胞培养方法，该方法可以用于特定的细胞类型，最终允许操纵该过程以产生感兴趣的细胞类型。定义 调节肌生成的分子途径无疑将形成新兴的新疗法， 再生策略

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