Determining the Role of Myrf in the Lung Mesothelium

确定 Myrf 在肺间皮中的作用

• 批准号: 10315975
• 负责人: Gidsela Luna
• 金额: $ 3.9万
• 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/10315975
• 关键词: Abdomen; Adult; 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 of activation protein; Mesenchymal; Mesoderm; Mesothelial Cell; Mesothelium; Molecular; Mutate; Mutation; Myelin; Nuclear; 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; base; body cavity; cardiac regeneration; cell behavior; cell type; experimental study; insight; lung development; 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 间皮细胞是中胚层来源的上皮细胞的单层，它包裹了许多我们的 内脏，包括肺。它的作用被认为是防止内脏滑动时的摩擦 其他的和身体的壁。它是否在发育和动态平衡中发挥其他作用，目前还知之甚少。在……里面 本研究中，我将通过询问转录因子Myrf的作用来研究间皮细胞的功能 在发育过程中在各种器官的间皮中表达的基因，包括肺。我走近 因为这个基因的变异已经在先天性横隔性疝气(CDH)中被发现，出生 与肺发育不良和肺动脉高压相关的缺陷。我发现Myrf在以下位置失活 肺发育的开始导致显著的CDH表型伴随肺发育不良。 在隔膜关闭之前。间皮细胞中表达的关键生长因子Fgf9的表达是 减少，提示Myrf功能在间皮细胞中是控制间皮细胞功能的一个来源 信号。相比之下，MyRF稍后在分枝阶段的失活导致了 间皮细胞分化成多个细胞层。这惊人地让人想起河马途径的表型 激酶基因LAT1/2在心外膜中失活，心外膜是心脏中相当于间皮细胞的细胞层。 与河马途径的参与一致，发现了下游的转录效应因子YAP 在Myrf突变体中，过剩的间皮细胞胞核中的表达增加。这些发现促使我提出 在发育过程中，Myrf通过调节生长信号的表达来控制间皮细胞的功能 (目标1)和河马-YAP信号通路的组成部分(目标2)。因为肺发育不全是关键 对于CDH患者的死亡原因，我的研究结果将促进我们对CDH发病机制的认识。