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 成年人的心脏缺乏再生能力。自成熟(成人)心肌细胞(CMS；心肌 细胞)是有丝分裂后的，心肌梗死后由心脏成纤维细胞(CFs)形成的纤维化瘢痕 不可逆转。这种疤痕经常导致左心功能不全和心力衰竭，这是 美国的死亡事件。最近的研究发现，哺乳动物新生儿的心脏具有显著的分解能力 损伤后会出现纤维化和再生。这一独特的现象可能在一定程度上是由CFS通过 新生儿心脏细胞外基质中的内在细胞内因子或通过外在信号。评估 已发表的RNA测序数据显示，在心脏中，两亲调节蛋白(即ARG)在 新生儿再生窗。AREG是一种促再生的细胞因子，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ARG的反应可能在高度不同的 再生的新生儿心脏。在这项研究中，我们将评估新生儿CFS对心脏修复的贡献。 (目标1)通过选择性细胞耗尽和RNA测序，同时确定它们对 促进再生的细胞因子，如ARG(AIM 2)，通过体内和体外研究。确立独特的角色 在新生儿心脏再生期间使用CFs将导致更有针对性的方法来对抗不可逆转的 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的培训计划，以 补充申请人建议的研究计划。心血管和心血管疾病的纵向临床选修课 再生医学将更好地理解这项研究的临床背景。在.之下 在发起人、论文委员会和咨询委员会的指导下，申请人将在以下方面发展她的知识 心血管研究中的实验设计、科学交流和技术。这项建议 在培训申请者成为临床科学家的同时，对心脏纤维化的当前知识做出贡献。