Determining the Role of Myrf in the Lung Mesothelium

确定 Myrf 在肺间皮中的作用

• 批准号: 10669220
• 负责人: Gidsela Luna
• 金额: $ 4.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669220
• 关键词: Abdomen; Adult; Binding; Birth; Cell Nucleus; Cells; Chest; Chromatin; Congenital Abnormality; Congenital diaphragmatic hernia; Data; Defect; Development; Disease; Embryo; Encapsulated; Epicardium; Epithelial Cells; Epitopes; FGF9 gene; Friction; Gene Expression; Genes; Genetic Transcription; Genetic study; Goals; Growth; Growth Factor; Heart; Homeostasis; Knock-in Mouse; Knowledge; Lubrication; Lung; Mediator; Mesenchymal; Mesoderm; Mesothelial Cell; Mesothelium; Molecular; Morphogenesis; Mutate; Mutation; Myelin; Nuclear; Oligodendroglia; Organ; Paracrine Communication; Pathway interactions; Patients; Pericytes; Phenotype; Phosphotransferases; Play; Pregnancy; Production; Pulmonary Hypertension; Respiratory Diaphragm; Role; Secondary to; Signal Pathway; Signal Transduction; Slide; Smooth Muscle Myocytes; Source; Squamous Epithelium; Surface; Testing; Tissues; Tretinoin; Variant; Vascular Smooth Muscle; WT1 gene; body cavity; cardiac regeneration; cardiac repair; cell behavior; cell type; experimental study; insight; lung development; lung regeneration; malformation; monolayer; mortality; mutant; prevent; pulmonary hypoplasia; single-cell RNA sequencing; transcription factor; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT The mesothelium is a monolayer of mesoderm-derived epithelial cells that encapsulates many of our internal organs, including the lung. Its ascribed role is to prevent friction as internal organs slide against each other and the body wall. Whether it plays other roles in development and homeostasis is poorly understood. In this study, I will investigate mesothelium function through interrogating the role of Myrf, a transcription factor gene expressed in the mesothelium of various organs, including the lung during development. I approached Myrf because variants in this gene have been identified in congenital diaphragmatic hernia (CDH), a birth defect associated with lung hypoplasia and pulmonary hypertension. I have found that inactivation of Myrf at the start of lung development resulted in a striking CDH phenotype accompanied by pulmonary hypoplasia prior to diaphragm closure. The expression of Fgf9, a key growth factor expressed in the mesothelium is reduced, suggesting that Myrf function in the mesothelium is to control mesothelium function as a source of signals. In comparison, inactivation of Myrf later on at the branching stage resulted in the expansion of the mesothelium into multiple cell layers. This is strikingly reminiscent of the phenotype when Hippo pathway kinase genes Lats 1/2 were inactivated in the epicardium, a mesothelium-equivalent cell layer in the heart. Consistent with an involvement of Hippo pathway, YAP, a downstream transcription effector, was found increased in the nucleus of the excess mesothelial cells in the Myrf mutant. These findings led me to propose that during development, Myrf controls mesothelium function by regulating the expression of growth signals (Aim 1) and components of the Hippo-YAP signaling pathway (Aim 2). Since pulmonary hypoplasia is a key cause of mortality in CDH patients, my findings will advance our knowledge on CDH disease mechanism.

项目摘要/摘要 间皮是中胚层衍生的上皮细胞的单层，它封装了我们的许多 内部器官，包括肺部。其归因的角色是防止摩擦作为内部器官滑动的摩擦 其他和身体墙。对发展和稳态中的其他作用是否扮演其他角色，对此也很熟悉。在 这项研究，我将通过询问MYRF的作用（转录因子的作用）来研究间皮功能 基因在发育过程中包括肺在内的各种器官的间皮中表达。我走近 MYRF是因为该基因中的变体已在先天性diaphragmatic Hernia（CDH）中鉴定出来， 与肺发育不全和肺动脉高压相关的缺陷。我发现Myrf失活 肺发育的开始导致CDH表型引人注目，并伴有肺部发育不全 在闭合膜片之前。 FGF9的表达，间皮中表达的关键生长因子是 减少，表明间皮中的MyRF功能是控制间皮功能作为来源 信号。相比之下，稍后在分支阶段灭活MYRF导致膨胀 间皮变成多个细胞层。这令人惊讶地让人联想到河马途径时表型 激酶基因纬度1/2在心脏的心脏上皮等效细胞层中被灭活。 与河马途径的参与一致，Yap是下游转录效应器 MYRF突变体中过量的间皮细胞的核增加。这些发现使我提出了 在开发过程中，MYRF通过调节生长信号的表达来控制间皮功能 （AIM 1）和河马信号通路的组件（AIM 2）。由于肺动脉症是关键 CDH患者死亡率的原因，我的发现将提高我们对CDH疾病机制的了解。