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Determining the Role of Myrf in the Lung Mesothelium

确定 Myrf 在肺间皮中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘