Regulators of extracellular matrix production during cardiac development and disease

心脏发育和疾病过程中细胞外基质产生的调节因子

基本信息

批准号：
10241540
负责人：
Onur Kanisicak
金额：
$ 40.5万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10241540
关键词：
Ablation Acute Acute Disease Acute myocardial infarction Adult Anatomy Angiotensins Back Biology Cardiac Cardiac development Cell Differentiation process Cell Lineage Cells Chronic Chronic Disease Cicatrix Collagen Data Deposition Development Disease Disease model Embryonic Development Endothelial Cells Exhibits Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Fibrosis Flow Cytometry Gene Expression Gene Expression Profile Genetic Goals Heart Heart Diseases Heart failure Heterogeneity Histologic Human Impairment Inflammatory Injury Isoproterenol Knock-out Label Ligands LoxP-flanked allele Mediator of activation protein Mesenchymal Minor Modeling Molecular Mus Myocardial Myocardial Infarction Myocardium Myofibroblast Outcome PDGFRB gene Pathologic Pericytes Perivascular Fibrosis Phase Play Population Process Production Proteins Reporter Reporting Role Rupture Series Source Testing Therapeutic Time Tissues Ventricular Vision Work base cell type constriction coronary fibrosis electrical property epithelial to mesenchymal transition experience experimental study gain of function in vivo innovation interstitial loss of function mechanical properties mouse model myocardial injury novel periostin pressure prevent single-cell RNA sequencing therapeutic target tool transcriptome sequencing

项目摘要

Cardiac fibrosis is a grim consequence for almost all myocardial injuries. In myocardial infarction (MI), what starts as a protective scarring process to prevent ventricular wall rupture becomes a pathological remodeling of the tissue with the accumulation of excess extracellular matrix (ECM) proteins. Eventually, this adaptation impedes the mechanical and electrical properties of the myocardium resulting in heart failure. Recently, we showed that periostin (Postn) expressing cells that arise from resident cardiac fibroblasts (CFs) are a potential therapeutic target since they differentiate into the scar associated, matrix-producing cell-type after MI injury. In fact, deletion of these cells after an acute MI injury eliminates interstitial fibrosis but results in ventricular rupture which is a hallmark outcome of impaired ECM deposition during the acute phase of MI. However, if we delete these cells during a chronic injury such as pressure overload-induced cardiac fibrosis model, we detect sustained perivascular fibrosis. Previous studies also report heterogeneity of origin and function for ECM-producing cells associated with different cardiac diseases. Consequently, our inability to identify cell- and state-specific therapeutic targets render cardiac fibrosis yet an incurable disease. Therefore, there is a critical need to determine the cellular composition and functional heterogeneity within ECM-producing fibroblasts. Until very recently, the main limitation has been the inability to accurately interrogate and manipulate the activities of different CF sub-populations differentiated from cells, including pericytes, endothelial cells, resident inflammatory cells in vivo given a lack of cell type-specific genetic tools. Recently, we and others have generated several novel genetic tools that now allow us to investigate all of the matrix-producing cells and their activated forms. Utilizing these new genetic tools in lineage tracing, gain-of-function, and loss-of-function studies, we will interrogate and determine the origin and function of all ECM-producing cell types as well as the molecular mechanisms that regulate CF sustained pathological activation and differentiation after acute or chronic disease models in mice. Our recent work where we effectively interrogated Postn expressing CF lineage in comparison to Postn negative CFs in a single-cell RNA sequencing analysis revealed distinct gene expression profiles between these two populations. Depending on the injury type, such as hearts subjected to MI, TAC, or Angiotensin induced fibrosis, we observed differences in ECM components as well as cellular composition. Finally, our preliminary data showed here identify another cell lineage that involves perivascular fibrosis. Therefore, we hypothesize that pathological ECM deposition resulting in fibrosis comes from disease-specific specialized sub-populations of CFs with distinct gene expressions. The following aims will rigorously interrogate CF subpopulations and the molecular mechanisms that regulate CF activation and ECM composition.

心脏纤维化是几乎所有心肌损伤的严峻后果。在心肌梗塞（MI）中，最初是一种防止心室壁破裂的保护性疤痕过程，成为一种病理随着过量细胞外基质（ECM）蛋白的积累的重塑。最终，这个适应阻碍心肌的机械和电性能导致心力衰竭。最近，我们表明骨膜蛋白（postn）表达由居民心脏成纤维细胞（CFS）引起的细胞是潜在的治疗靶标，因为它们分化为相关的疤痕产生基质的细胞类型 Mi受伤后。实际上，急性MI损伤后这些细胞的缺失消除了间质纤维化，但导致心室破裂是MI急性期ECM沉积受损的标志结果。但是，如果我们在慢性损伤中删除这些细胞，例如压力超负荷引起的心脏纤维化模型，我们检测到持续的血管周纤维化。先前的研究还报告了起源的异质性和与不同心脏病相关的产生ECM的细胞的功能。因此，我们无法鉴定细胞和特异性的治疗靶标使心脏纤维化导致然而，一种无法治愈的疾病。因此，确定细胞组成和功能的迫切需要产生ECM的成纤维细胞中的异质性。直到最近，主要限制一直无法准确询问和操纵与细胞不同的不同CF亚群的活性，包括细胞类型特异性的细胞类型，包括周细胞，内皮细胞，驻留炎症细胞遗传工具。最近，我们和其他人生成了几种新颖的遗传工具，现在使我们能够研究所有产生基质的细胞及其活化形式。利用这些新的遗传工具谱系追踪，功能获得和功能丧失研究，我们将询问并确定起源和所有产生ECM细胞类型的功能以及调节CF持续的分子机制小鼠急性或慢性病模型后的病理激活和分化。我们最近的工作与单细胞中的Postn负CF相比 RNA测序分析揭示了这两个群体之间的不同基因表达谱。根据损伤类型，例如受到MI，TAC或血管紧张素诱导纤维化的心脏，我们观察到ECM成分以及细胞组成的差异。最后，我们的初步数据显示在这里确定另一个涉及血管周纤维化的细胞谱系。因此，我们假设导致纤维化的病理ECM沉积来自于疾病特异性的专业亚人群具有不同基因表达的CF。以下目标将严格询问CF亚群，并调节CF激活和ECM组成的分子机制。