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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

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.

摘要长期以来，心肌细胞一直是试图阐明心肌细胞凋亡的研究的主要焦点。心脏发育和疾病的潜在调节方面。然而，最近，非肌细胞的参与可能与肌细胞一样重要，在发育和进行性过程中促进和控制心脏重塑缺血性心力衰竭的发病机制。更具体地说，心脏成纤维细胞及其转化为肌成纤维细胞的能力，促进ECM的产生，心室重塑和纤维化反应作为心脏生物学的关键调节因子一直未得到充分重视。这里我们提出由发育和成人疾病心脏研究者领导的双PI应用以解决成纤维细胞生物学的关键领域，从出生后的早期心脏到失败的心脏，和成人心脏纤维化在此之前，该字段无法仔细注释函数在发育和患病的心脏内的成纤维细胞方面，部分原因是缺乏专门针对这种细胞类型的合适的遗传工具。最近，我们和其他人产生了一些关键的转基因小鼠模型，专门针对常驻心脏成纤维细胞，以及心脏中所有活化的成纤维细胞和肌成纤维细胞。因此，在这里我们可以现在测试激活的成纤维细胞和肌成纤维细胞发挥作用的新的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，其在成人心脏中再现，以响应急性和慢性缺血诱导的疾病 states.双PI应用程序有3个具体目标：1）定义子阶段和功能，出生后发育和成年心脏中的心脏成纤维细胞和肌成纤维细胞在急性和慢性疾病刺激后，2）为了识别在发育和患病心脏中的心脏成纤维细胞和肌细胞，和3）为了定义Tcf 21- 介导的贡献，成纤维细胞谱系扩增和承诺，在发展中国家，出生后心脏和成人心脏缺血和急性损伤后。总体而言，这些具体目的将揭示成纤维细胞在发育，再生和分化过程中的阶段。间质性纤维化和替代性纤维化两种模型中的肥大。这样的了解将为未来研究特定的治疗途径奠定基础，在治疗长期纤维化心脏病状态或增强再生能力，心脏