Myovascular Mechanisms of Cardiac Growth and Regeneration

心脏生长和再生的肌血管机制

基本信息

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
项目类别：
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

项目摘要

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.

抽象的：我们和其他人已经确定心肌细胞 (CM) 增殖依赖于心脏内皮细胞细胞（CEC）。新生小鼠中增殖的 CEC 与增殖的 CM 存在时空耦合心; CEC 的缺失导致 CM 增殖减少；和更高水平的主要血管生成因子 Vegfa 促进斑马鱼、新生小鼠和人类的心脏生长。基于这些研究，我们总体假设是激活的、增殖的 CEC 指导 CM 增殖。在此，我们提出研究确定 CEC 如何促进 CM 增殖。我们将使用 scRNA-seq 和空间建模来识别与增殖的 CM 物理相关的 CEC 的特定子集；我们将确定 Ezh2- 介导的染色质重塑协调 CEC 激活与 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，具有很高的信息潜力治疗性心脏再生的方法。