Macrophage functional dynamics in adult heart regeneration

成人心脏再生中巨噬细胞的功能动态

基本信息

批准号：
10658366
负责人：
Jiandong Liu
金额：
$ 59.68万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658366
关键词：
Acceleration Acute Address Adult Affect Alternative Splicing Antibodies Basic Science Behavior Binding Biological Biological Process Biology CRISPR/Cas technology Cardiac Cardiac Myocytes Cell Communication Cells Chromatin Cicatrix Communication Complex Data Data Analyses Development Endothelial Cells Event Exhibits Fibroblasts Functional disorder Future Gene Expression Genetic Genomic approach Health Heart Heart Diseases Heart failure Homeostasis Human Immune Immunologic Surveillance Individual Inflammation Inflammatory Inflammatory Response Label Macrophage Messenger RNA Molecular Morbidity - disease rate Myocardial Infarction Myocardial Ischemia Myocardium Natural regeneration Outcome Phenotype Physiology Play Population Process Proliferating Publishing RNA RNA Splicing Regenerative capacity Research Proposals Resolution Role Shapes Signal Transduction Spatial Distribution Study models TNF gene Testing Therapeutic Intervention Time Transcription Factor AP-1 Transcriptional Regulation Transgenic Organisms United States Zebrafish cardiac regeneration cardiogenesis cell determination cell type genetic manipulation heart damage immune function improved insight mortality mutant myocardial injury public health relevance regenerative response single-cell RNA sequencing therapeutic development tool transcription factor transcriptome transcriptomics

项目摘要

Much of the basic research on cardiac biology has been focused on cardiomyocytes (CMs), aiming to unravel the basic principles underlying cardiac physiology and pathophysiology for future development of therapeutic interventions to treat cardiac diseases. Besides CMs, the heart contains many other cell types including endothelial cells, fibroblasts, and a wide variety of immune cells. During heart development and homeostasis, non-myocytes (nonCMs) have been increasingly recognized to play active roles in regulating various CM behaviors. Yet a lack of detailed information on the cellular identities and cell states of the nonCMs associated development and homeostasis is a major hurdle to precisely delineating the biological events in heart development and homeostasis. In our recently published study, we delineated nonCMs cellular and transcriptomic dynamics during cardiac regeneration. Through scRNA-seq, we identified major nonCM cell types, including multiple macrophage (MC), FB and EC subpopulations with unique tempo-spatial distribution. Prticularly, we found that MC exists in multiple definable states that exhibit dynamic functional changes from acute inflammatory response to inflammation resolution. Interestingly, perturbing MC function resulted in defective cardiac regeneration. Combining Topologizer and RNA velocity analyses, we uncovered dynamic transition between MC functional states and identified factors involved in mRNA processing and transcriptional regulation associated with the transition. However, whether and how nonCMs interact at the subpopulation level, and MC dynamic functional change affects nonCMs interactions and hence heart regeneration remains largely unexplored. In this research proposal, we hypothesize that heart regeneration is a highly orchestrated process involving temporally regulated MC function executed by the distinct subtypes and their interactions with other nonCM cell types. To test this hypothesis, we aim to 1) define the role of the inflammatory MCs (iMCs) subtype in nonCM interaction and heart regeneration, 2) delineate the role of the immune surveillance MC (isMCs) subtype in nonCM interaction and heart regeneration, and 3) study the molecular mechanism governing transition of MC functional states.

心脏生物学的大部分基础研究都集中在心肌细胞（CM）上，旨在解开心脏生理学和病理生理学的基本原理，用于未来治疗的发展治疗心脏病的干预措施。除了 CM 之外，心脏还含有许多其他细胞类型，包括内皮细胞、成纤维细胞和多种免疫细胞。在心脏发育和体内平衡过程中，人们越来越认识到非肌细胞 (nonCM) 在调节各种 CM 中发挥积极作用行为。然而，缺乏有关相关非CM的细胞身份和细胞状态的详细信息发育和稳态是精确描述心脏生物事件的主要障碍发育和稳态。在我们最近发表的研究中，我们描述了非 CM 细胞和心脏再生过程中的转录组动力学。通过 scRNA-seq，我们确定了主要的非 CM 细胞类型，包括具有独特时空分布的多个巨噬细胞（MC）、FB和EC亚群。特别是，我们发现 MC 存在于多种可定义状态中，这些状态表现出动态功能变化急性炎症反应至炎症消退。有趣的是，扰乱 MC 功能会导致有缺陷的心脏再生。结合拓扑分析器和 RNA 速度分析，我们发现了动态 MC 功能状态之间的转变和已确定的参与 mRNA 加工和转录的因素与过渡相关的监管。然而，非CM是否以及如何在亚群体水平上相互作用， MC 动态功能变化影响非 CM 相互作用，因此心脏再生在很大程度上仍然存在未经探索。在这项研究提案中，我们假设心脏再生是一个高度精心策划的过程涉及由不同亚型执行的时间调节 MC 功能及其与其他亚型的相互作用非CM细胞类型。为了检验这一假设，我们的目标是 1) 定义炎症 MC (iMC) 亚型的作用在非 CM 相互作用和心脏再生中，2) 描述免疫监视 MC (isMCs) 的作用非CM相互作用和心脏再生的亚型，以及3）研究控制的分子机制 MC 功能状态的转换。