Myovascular Mechanisms of Cardiac Growth and Regeneration

心脏生长和再生的肌血管机制

• 批准号: 10543183
• 负责人: RAVI KARRA
• 金额: $ 52.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543183
• 关键词: Adult; Angiogenic Factor; Biological Assay; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Count; Cell Cycle; Cell Proliferation; Cells; Cellular Assay; Chromatin; Chromatin Remodeling Factor; Coupled; Data; Defect; Development; Endothelial Cells; Epigenetic Process; Genes; Genetic; Goals; Growth; Growth Factor; Heart; Heart failure; Histologic; Human; Hyperplasia; In Vitro; Knowledge; Licensing Factor; Life; Link; Longevity; LoxP-flanked allele; Maps; Mediating; Mediator; Methods; Mitogens; Modeling; Mus; Myocardial; Natural regeneration; Neonatal; Outcome; Phenotype; Population; Proliferating; Role; Therapeutic; Transposase; Up-Regulation; VEGFA gene; Vascular Endothelial Growth Factors; Work; Zebrafish; cardiac regeneration; cell type; chromatin remodeling; experimental study; histone methyltransferase; improved; in vivo; neonatal mice; neonatal period; overexpression; paracrine; postnatal; receptor; response; single-cell RNA sequencing; spatiotemporal; therapeutic target

ABSTRACT: We, and others, have determined that cardiomyocyte (CM) proliferation is dependent on cardiac endothelial cells (CECs). Proliferating CECs are spatiotemporally coupled to proliferating CMs in the neonatal mouse heart; loss of CECs leads to decreased CM proliferation; and higher levels of the master angiogenic factor Vegfa promote cardiac growth in zebrafish, neonatal mice, and humans. Based on these studies, our overall hypothesis is that activated, proliferating CECs instruct CM proliferation. Here, we propose studies to determine how CECs promote CM proliferation. We will use scRNA-seq and spatial modeling to identify the specific subset of CECs physically associated with proliferating CMs; we will determine how Ezh2- mediated chromatin remodeling coordinates CEC activation with CM proliferation; and we will define the potency of CEC-induced growth factors to stimulate CM proliferation. This work will result in new cellular, epigenetic, and paracrine mechanisms for CEC-induced cardiac growth and has high potential to inform methods for therapeutic heart regeneration.

摘要： 我们和其他人已经确定心肌细胞(CM)的增殖依赖于心肌内皮细胞 细胞(CECs)。新生小鼠增殖的内皮细胞与增殖的CMS的时空偶联 心脏；内皮细胞缺失导致心肌细胞增殖减少；主血管生成因子水平升高 VEGFA促进斑马鱼、新生小鼠和人类的心脏生长。基于这些研究，我们的 总体假设是活化的、增殖的CEC引导CM增殖。在这里，我们建议进行研究 以确定CEC如何促进CM的增殖。我们将使用scrna-seq和空间建模来识别 与CMS增殖有关的CEC的特定子集；我们将确定Ezh2- 介导的染色质重塑协调CEC激活和CM增殖；我们将定义 CEC诱导的生长因子刺激CM增殖的效力。这项工作将产生新的细胞， CEC诱导的心脏生长的表观遗传和旁分泌机制，具有很高的潜在信息 治疗心脏再生的方法。