Cardiac fibroblasts in postnatal development and adult injury response

心脏成纤维细胞在产后发育和成人损伤反应中的作用

基本信息

批准号：
10217231
负责人：
Jeffery D Molkentin
金额：
$ 68.72万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217231
关键词：
Acute Acute Disease Address Adult Affect Area Biology Cardiac Cardiac Myocytes Cardiac development Cell Lineage Cells Cellular biology Chronic Chronic Disease Cicatrix Collagen Complementary DNA Development Disease Disease Progression Disease regression Extracellular Matrix Fibroblasts Fibrosis Foundations Future Gene Expression Genes Genetic Goals Growth Heart Heart Diseases Heart Hypertrophy Heart Injuries Heart failure Histologic Hypertrophy Injury Ischemia Knock-in Mouse Knowledge Longevity Mediating Modeling Mus Muscle Cells Myofibroblast Natural regeneration Neonatal Organ Pathogenesis Pathologic Pathway interactions Patients Play Production Regenerative capacity Regulation Research Personnel Resolution Rest Role Signal Transduction Smooth Muscle Stress Tamoxifen Testing Therapeutic Time Undifferentiated Ventricular Ventricular Remodeling alpha Actin base cardiac repair cardiogenesis cell type coronary fibrosis genomic locus healing heart function injured interstitial loss of function mouse model new therapeutic target novel novel therapeutics periostin postnatal postnatal development progenitor ranpirnase receptor response response to injury single-cell RNA sequencing tool transcription factor

Acute Acute Disease Address Adult Affect Area Biology Cardiac Cardiac Myocytes Cardiac development Cell Lineage Cells Cellular biology Chronic Chronic Disease Cicatrix Collagen Complementary DNA Development Disease Disease Progression Disease regression Extracellular Matrix Fibroblasts Fibrosis Foundations Future Gene Expression Genes Genetic Goals Growth Heart Heart Diseases Heart Hypertrophy Heart Injuries Heart failure Histologic Hypertrophy Injury Ischemia Knock-in Mouse Knowledge Longevity Mediating Modeling Mus Muscle Cells Myofibroblast Natural regeneration Neonatal Organ Pathogenesis Pathologic Pathway interactions Patients Play Production Regenerative capacity Regulation Research Personnel Resolution Rest Role Signal Transduction Smooth Muscle Stress Tamoxifen Testing Therapeutic Time Undifferentiated Ventricular Ventricular Remodeling alpha Actin base cardiac repair cardiogenesis cell type coronary fibrosis genomic locus healing heart function injured interstitial loss of function mouse model new therapeutic target novel novel therapeutics periostin postnatal postnatal development progenitor ranpirnase receptor response response to injury single-cell RNA sequencing tool transcription factor

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项目摘要

Abstract The cardiac myocyte has long been the primary focus of studies attempting to elucidate the regulatory aspects underlying cardiac development and disease. However, recently the involvement of nonmyocytes has emerged as potentially just as important as myocytes in contributing to and controlling cardiac remodeling during development and progressive pathogenesis in ischemia-induced heart failure. More specifically, the cardiac fibroblast and its ability to convert to myofibroblasts in promoting ECM production, ventricular remodeling and the fibrotic response have been underappreciated as critical regulator of cardiac biology. Here we propose a dual-PI application led by developmental and adult disease-based cardiac investigators to address key areas of fibroblast biology that span the early postnatal heart up through the failing and fibrotic adult heart. Previously, the field had not been able to carefully annotate the functional aspects of the fibroblast within the developing and diseased heart, in part because of a lack of appropriate genetic tools that specifically target this cell-type. More recently we and others have generated a few critical genetically modified mouse models that specifically target resident cardiac fibroblasts, as well as all activated fibroblasts and myofibroblasts in the heart. Thus, here we can now test the novel and overarching hypothesis that activated fibroblasts and myofibroblasts play selective roles in early neonatal ventricular maturation, regeneration and heart development, which is recapitulated in the adult heart in response acute and chronic ischemia-induced disease states. The dual-PI application has 3 specific aims: 1) To define sub-stages and functions of cardiac fibroblasts and myofibroblasts during postnatal development and in the adult heart following acute and chronic disease stimulation, 2) To identify crosstalk mechanisms between cardiac fibroblasts and myocytes in the developing and diseased heart, and 3) To define Tcf21- mediated contributions to fibroblast lineage expansion and commitment in the developing postnatal heart and in the adult heart after ischemic and acute injury. Collectively, these specific aims will uncover stages of fibroblast differentiation during development, regeneration and hypertrophy across both models of interstitial fibrosis and replacement fibrosis. Such an understanding will lay the foundation for future studies into specific therapeutic pathways to target in treating longstanding fibrotic heart disease states or to enhance the regenerative capacity of the heart.

抽象的长期以来，心肌细胞一直是试图阐明该研究的主要重点心脏发展和疾病的基础监管方面。但是，最近非甲状腺细胞的参与可能与肌细胞同样重要在开发过程和进步期间为心脏重塑做出贡献和控制缺血引起的心力衰竭的发病机理。更具体地说，心脏成纤维细胞及其能够转化为促进ECM产生，心室重塑和纤维化反应被低估为心脏生物学的关键调节剂。我们在这里提出由发展和成人基于疾病的心脏研究者领导的双PI应用解决成纤维细胞生物学的关键领域，这些领域跨越了早期产后心脏。和纤维化成人心脏。以前，该领域无法仔细注释功能发育中和患病的心脏中成纤维细胞的各个方面，部分原因是缺乏专门针对该细胞类型的适当遗传工具。最近我们和其他人有产生了一些关键的转基因鼠标模型，这些模型专门针对居民心脏成纤维细胞以及心脏中所有活化的成纤维细胞和肌纤维细胞。因此，我们可以现在测试激活成纤维细胞和肌纤维细胞发挥的小说和总体假设在早期新生儿心室成熟，再生和心脏发育中的选择性作用，在成人心脏中概括的急性和慢性缺血诱导的疾病国家。双PI应用程序具有3个特定目的：1）定义子阶段和功能心脏成纤维细胞和肌纤维细胞在产后发育和成人心脏急性和慢性疾病刺激后，2）确定串扰机制发育中和患病的心脏中的心脏成纤维细胞和心肌细胞，以及3）定义TCF21- 对成纤维细胞谱系扩展和发育中的承诺的介导的贡献缺血性和急性损伤后产后心脏和成人心脏中。总的来说，这些具体目标将在开发，再生和两种间隙纤维化和替代纤维化模型的肥大。这样的理解将为未来的研究奠定基础在治疗长期存在的纤维化心脏病状态或增强再生能力心。