Defining the Unique Role of Fibroblasts in Neonatal Cardiac Regeneration

项目摘要 成年人的心脏缺乏再生能力。由于成熟（成体）心肌细胞（CM;心肌 细胞）是有丝分裂后的，心肌梗死后由心脏成纤维细胞（CF）形成的纤维化瘢痕是 不可逆的这种疤痕通常会导致左心室功能障碍和心力衰竭，这是心脏病的主要原因。 死亡在美国最近的研究发现，哺乳动物新生儿心脏具有非凡的分辨能力， 纤维化并在损伤后再生。这种独特的现象可能部分由CF介导， 内源性细胞内因子或通过新生儿心脏细胞外基质中的外源性信号。评价 已发表的RNA测序数据揭示了双调蛋白（即Areg）在心脏中的富集， 新生儿再生窗Areg是一种促再生细胞因子，也被证明可以刺激CF 心脏的增生和纤维化。然而，细胞对Areg的反应可能在高浓度下是不同的。 新生儿心脏再生在这项研究中，我们将评估新生儿CF对心脏修复的贡献 (Aim 1）通过选择性细胞耗竭和RNA测序，同时确定它们对以下的反应： 促再生细胞因子，如Areg（Aim 2）通过体内和体外研究。发挥独特作用 新生儿心脏再生过程中CFs的减少将导致更有针对性的方法来对抗不可逆的 成人心脏损伤后出现心脏纤维化。该提案还详细说明了临床活动的培训计划， 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，申请人将在以下方面发展她的知识： 心血管研究的实验设计、科学交流和技术。这项建议 有助于心脏纤维化的当前知识，同时培训申请人成为临床科学家。

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.