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.

关于心脏生物学的大部分基础研究都集中在心肌细胞（CMS）上，旨在解开治疗的未来发展的心脏生理学和病理生理学的基本原理治疗心脏病的干预措施。除CMS外，心脏还包含许多其他细胞类型，包括内皮细胞，成纤维细胞和多种免疫细胞。在心脏发展和稳态期间，非肌细胞（NONCMS）已被越来越多地认识到在调节各种CM中起积极作用行为。然而，缺乏有关相关的NONCMS的细胞身份和细胞状态的详细信息发展和体内平衡是精确描述心脏中生物事件的主要障碍发展和体内平衡。在我们最近发表的研究中，我们描述了Noncms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，包括多个巨噬细胞（MC），FB和EC亚群，具有独特的速度空间分布。概论地，我们发现MC存在于多个可确定状态，这些状态表现出动态功能变化。急性炎症反应对炎症分辨率。有趣的是，扰动MC功能导致心脏再生缺陷。结合拓扑器和RNA速度分析，我们发现了动态 MC功能状态与鉴定出参与mRNA加工和转录的因素之间的过渡与过渡相关的调节。但是，非CMS是否以及如何在亚种群水平上相互作用， MC动态功能变化会影响NONCMS的相互作用，因此心脏再生在很大程度上仍然存在未探索。在这项研究建议中，我们假设心脏再生是一个精心策划的过程涉及由不同的子类型执行的时间调节的MC函数及其与其他的相互作用 NONCM细胞类型。为了检验这一假设，我们的目的是1）定义炎症MCS（IMC）亚型的作用在NonCM相互作用和心脏再生中，2）描述免疫监视MC（ISMC）的作用非CM相互作用和心脏再生中的亚型，3）研究分子机制 MC功能状态的过渡。