Defining the Unique Role of Fibroblasts in Neonatal Cardiac Regeneration

定义成纤维细胞在新生儿心脏再生中的独特作用

基本信息

批准号：
10065790
负责人：
Adwiteeya Misra
金额：
$ 5.05万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10065790
关键词：
Acute Adult Advisory Committees Affect Age-Years American Amphiregulin Apical Apoptosis Attenuated Cardiac Cardiac Myocytes Cardiovascular system Cause of Death Cells Chronic Cicatrix Clinical Communication Complement Coronary Vessels Cues Data Dependovirus Development Diphtheria Toxin Evaluation Excision Experimental Designs Extracellular Matrix Fibroblasts Fibrosis Functional disorder Gene Expression Profile Genetic Transcription Goals Heart Heart Injuries Heart failure In Vitro Inflammatory Injury Knowledge Label Lead Left Ventricular Dysfunction Lung Mediating Mitotic Modeling Mus Myocardial Infarction Myocardium Natural regeneration Neonatal Palliative Care Pathologic Play Preventive treatment Process Production Public Health Publishing RNA Regenerative Medicine Research Resolution Role Scientist Serotyping Signal Transduction Skeletal Muscle Subfamily lentivirinae Supplementation Techniques Testing Therapeutic Tissues Training Work Zebrafish alpha Toxin cardiac regeneration cardiac repair combat coronary fibrosis cytokine extracellular heart function improved in vivo overexpression postnatal recruit regenerative response transcriptome transcriptome sequencing transcriptomics

项目摘要

Project Summary Adult hearts lack the capacity to regenerate. Since mature (adult) cardiomyocytes (CMs; cardiac muscle cells) are post-mitotic, the fibrotic scar formed by cardiac fibroblasts (CFs) after a myocardial infarction is irreversible. This scar often contributes to left ventricular dysfunction and heart failure, the leading causes of death in US. Recent studies have found that the mammalian neonatal heart has a remarkable capacity to resolve fibrosis and regenerate after an injury. This unique phenomenon may be mediated, in part, by CFs through intrinsic intracellular factors or via extrinsic signals in the neonatal cardiac extracellular matrix. Evaluation of published RNA-sequencing data has revealed an enrichment of Amphiregulin (i.e. Areg) in the heart during the neonatal regenerative window. Areg is a pro-regenerative cytokine that has been also shown to stimulate CF proliferation and fibrosis in the adult heart. However, the cellular responses to Areg may be different in the highly regenerative neonatal heart. In this study, we will evaluate the contributions of neonatal CFs to cardiac repair (Aim 1) through selective cell depletion and RNA sequencing while simultaneously defining their response to pro-regenerative cytokines such as Areg (Aim 2) through in vivo and in vitro studies. Establishing the unique role of CFs during neonatal cardiac regeneration will lead to more targeted approaches to combat the irreversible cardiac fibrosis present after adult cardiac injury. This proposal also details a training plan of clinical activities to complement the proposed research plan of the applicant. The longitudinal clinical electives in cardiovascular and regenerative medicine will provide a better understanding of the clinical context of the research. Under the guidance of the sponsor, thesis committee, and advisory committee, the applicant will develop her knowledge in experimental design, scientific communications, and techniques in cardiovascular research. This proposal contributes to current knowledge in cardiac fibrosis while training the applicant to be a clinician-scientist.

项目概要成人心脏缺乏再生能力。由于成熟（成年）心肌细胞（CM；心肌细胞）是有丝分裂后的，心肌梗塞后由心脏成纤维细胞（CF）形成的纤维化疤痕是不可逆转的。这种疤痕通常会导致左心室功能障碍和心力衰竭，这是左心室功能障碍和心力衰竭的主要原因在美国死亡。最近的研究发现，哺乳动物新生儿心脏具有非凡的解决问题的能力纤维化并在受伤后再生。这种独特的现象可能部分是由CFs介导的内在的细胞内因子或通过新生儿心脏细胞外基质中的外在信号。评价已发表的 RNA 测序数据显示，心脏中双调蛋白（即 Areg）在心脏中富集。新生儿再生窗口。 Areg 是一种促再生细胞因子，也被证明可以刺激 CF 成人心脏的增殖和纤维化。然而，细胞对 Areg 的反应可能在高度不同的情况下有所不同。再生新生儿心脏。在这项研究中，我们将评估新生儿 CF 对心脏修复的贡献（目标 1）通过选择性细胞去除和 RNA 测序，同时定义它们对通过体内和体外研究发现促再生细胞因子，例如 Areg（目标 2）。建立独特的角色新生儿心脏再生过程中 CF 的研究将导致更有针对性的方法来对抗不可逆转的疾病成人心脏损伤后出现心脏纤维化。该提案还详细介绍了临床活动培训计划，以补充申请人提出的研究计划。心血管和心血管疾病的纵向临床选修课再生医学将使人们更好地了解该研究的临床背景。下在赞助商、论文委员会和咨询委员会的指导下，申请人将发展她的知识心血管研究中的实验设计、科学交流和技术。这个提议有助于增进心脏纤维化的当前知识，同时将申请人培训为临床医生科学家。