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

• 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
• 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

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.

项目摘要 成人心缺乏再生能力。由于成熟（成人）心肌细胞（CMS；心肌 细胞）是有丝分裂后，是心肌梗塞后由心脏成纤维细胞（CFS）形成的纤维化疤痕 不可逆转。这种疤痕通常导致左心室功能障碍和心力衰竭，这是 我们的死亡。最近的研究发现，哺乳动物新生儿心脏具有明显的解决能力 受伤后的纤维化和再生。这种独特的现象可能部分由CFS通过 新生儿心脏外基质中的内部细胞内因子或通过外在信号。评估 已发表的RNA - 序列数据揭示了在心脏中富集了两性凝胶蛋白（即AREG）。 新生儿再生窗口。 AREG是一种促再生细胞因子，也已证明可以刺激CF 成人心脏的增殖和纤维化。但是，对AREG的细胞反应在高度中可能有所不同 再生新生儿心脏。在这项研究中，我们将评估新生儿CFS对心脏修复的贡献 （AIM 1）通过选择性细胞耗竭和RNA测序，同时定义它们对 促进性细胞因子（例如AREG（AIM 2））通过体内和体外研究。建立独特的角色 新生儿心脏再生期间的CFS将导致更具针对性的方法来对抗不可逆的 成人心脏损伤后存在心脏纤维化。该建议还详细介绍了临床活动的培训计划 补充申请人提议的研究计划。心血管和 再生医学将更好地了解研究的临床背景。在 赞助商，论文委员会和咨询委员会的指导，申请人将发展她的知识 心血管研究中的实验设计，科学通信和技术。这个建议 在训练申请人成为临床医生的同时，有助于心脏纤维化的当前知识。