Forkhead Transcription Factor is required for Cardiomyocyte Proliferation

心肌细胞增殖需要叉头转录因子

• 批准号: 10238940
• 负责人: Daniel Anthony Zuppo
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-30 至 2022-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238940
• 关键词: Address; Adult; Affect; Amputation; Attenuated; Automobile Driving; Cancer Model; Cardiac; Cardiac Myocytes; Cause of Death; Cell Culture Techniques; Cell Cycle Progression; Cell Lineage; Cell Nucleus; Cell Proliferation; Cessation of life; Childhood; Cicatrix; Coronary; Coronary artery; Cyclin B; Cytoplasm; DUSP6 protein; Data; Diploidy; ERBB2 gene; Excision; FOXM1 gene; Fibrosis; Gene Expression Profiling; Genes; Genetic; Genetic Epistasis; Genetic Transcription; Goals; Heart; Heart Diseases; Heart Injuries; Injury; MAP Kinase Gene; MAPK Signaling Pathway Pathway; Mammals; Mediating; Mitotic; Modeling; Molecular; Morbidity - disease rate; Myocardial Infarction; Natural regeneration; Nuclear Translocation; Pathway interactions; Patients; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Process; Proliferating; Receptor Protein-Tyrosine Kinases; Regenerative response; Regulator Genes; Resolution; Role; Signal Transduction; System; Testing; Therapeutic; Tissues; United States; Ventricular; Work; Zebrafish; angiogenesis; cardiac regeneration; cardiac repair; cdc Genes; epithelial to mesenchymal transition; forkhead protein; heart damage; improved; insight; ischemic injury; loss of function; mutant; overexpression; repaired; response; transcription factor; transcriptome; transcriptome sequencing; tumorigenesis

Project Summary/Abstract Myocardial infarction results from ischemic injury to the coronary arteries, and triggers localized cardiomyocyte (CM) death as well as turnover of damaged cardiac tissue into fibrotic tissue. Adult mammalian CMs fail to sufficiently proliferate post-injury and allow for persistent fibrosis within the heart which elevates patient morbidity. Heart disease remains the leading cause of death in the United States and current therapeutics only attenuate the progression of heart disease: they cannot reverse cardiac damage by inducing CM proliferation. However, it may be possible to stimulate adult CM proliferation as mono- and bi-nucleated CMs were recently shown to proliferate in post-natal, young, mammalian hearts. Therefore, it is imperative to discern the mechanisms driving CM proliferation and if their manipulation can improve pediatric and adult CM proliferation and cardiac regeneration. In this proposal, we will utilize a ventricular amputation model in adult zebrafish to study cardiac regeneration. Adult zebrafish CMs are mono-nucleated, diploid, and display robust proliferation after injury which makes them ideal to identify and study the molecular mechanisms regulating CM proliferation. Using transcriptome profiling (RNA-Seq) after ventricular resection, we identified that Forkhead box M1, Foxm1, expression increased during the early stages of cardiac regeneration. The goals of this proposal are to determine the role of Foxm1 in cardiac regeneration and CM proliferation. We will utilize loss- of-function approaches to study foxm1 mutants after cardiac injury. In addition, we will address the question whether Foxm1 is activated by the Ras/MAPK signaling axis, and investigate downstream foxm1 target genes via transcriptional profiling. These studies will be critical in understanding how CMs are activated to become mitotic after injury. Understanding these intricate mechanisms will provide us with new insights to stimulate cardiomyocyte proliferation and discover genetic targets to enhance cardiac regeneration in mammalian systems.

项目总结/摘要 心肌梗死是冠状动脉缺血性损伤的结果， (CM)死亡以及受损心脏组织转变为纤维化组织。成年哺乳动物CM不能 在损伤后充分增殖，并允许心脏内持续纤维化， 发病率心脏病仍然是美国的主要死亡原因，目前的治疗方法只 减缓心脏病的进展：它们不能通过诱导CM增殖来逆转心脏损伤。 然而，它可能会刺激成年CM增殖，因为单核和双核CM最近被发现， 在出生后年轻哺乳动物的心脏中增殖因此，当务之急是辨别 驱动CM增殖的机制，以及它们的操作是否可以改善儿童和成人CM增殖 和心脏再生在这个提议中，我们将利用成年斑马鱼的心室截肢模型， 研究心脏再生。成年斑马鱼CM是单核的、二倍体的，并且显示出稳健的增殖 这使得它们成为鉴定和研究调节CM的分子机制的理想选择 增殖在心室切除术后使用转录组分析（RNA-Seq），我们确定Forkhead box M1，Foxm 1，在心脏再生的早期阶段表达增加。这个的目标 该研究的目的是确定Foxm 1在心脏再生和CM增殖中的作用。我们会利用损失- 研究心脏损伤后foxm 1突变体的功能方法。此外，我们还将讨论 Foxm 1是否被Ras/MAPK信号轴激活，并研究下游foxm 1靶基因 通过转录分析。这些研究对于理解CM是如何被激活成为 损伤后有丝分裂。了解这些错综复杂的机制将为我们提供新的见解， 哺乳动物心肌细胞增殖和发现促进心脏再生遗传靶点 系统.