Macrophage functional dynamics in adult heart regeneration

成人心脏再生中巨噬细胞的功能动态

• 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
• 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

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.

心脏生物学的许多基础研究都集中在心肌细胞（CM）上，旨在揭示 心脏生理学和病理生理学的基本原则，为未来的治疗发展 治疗心脏病的干预措施。除了CM，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， 非肌细胞（non-myocytes，nonCM）在各种CM的调控中发挥着重要作用 行为。然而，缺乏有关非CM相关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学事件的主要障碍 发育和体内平衡。在我们最近发表的研究中，我们描述了非CM细胞， 心脏再生过程中的转录动力学。通过scRNA-seq，我们鉴定了主要的非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。 特别地，我们发现MC存在于多个可定义的状态中，这些状态表现出动态的功能变化， 急性炎症反应至炎症消退。有趣的是，干扰MC功能导致 心脏再生缺陷结合Topologizer和RNA速度分析，我们发现了动态 MC功能状态与参与mRNA加工和转录的已鉴定因子之间的转换 与转型相关的监管。然而，非CM是否以及如何在亚群水平上相互作用， 而MC的动态功能变化影响非CM的相互作用，因此心脏再生在很大程度上仍然存在。 未开发的在这项研究计划中，我们假设心脏再生是一个高度协调的过程 涉及由不同亚型执行的时间调节的MC功能及其与其他亚型的相互作用， 非CM细胞类型。为了验证这一假设，我们的目标是：1）定义炎性MC（iMC）亚型的作用， 在非CM相互作用和心脏再生中，2）描述了免疫监视MC（isMCs）的作用 亚型在非CM相互作用和心脏再生，和3）研究的分子机制， MC功能状态的转变。