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Effect of Neonatal Hyperoxia on Alveolar Development and Infection

新生儿高氧对肺泡发育和感染的影响

基本信息

批准号：
9767838
负责人：
Michael A O'Reilly
金额：
$ 53.66万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-10 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767838
关键词：
Adult Affect Air Alveolar Birth Cartoons Cell Death Cell Proliferation Cells Cessation of life Development Environment Environmental Risk Factor Epigenetic Process Epithelial Epithelial Cells Exposure to Funding Gene Expression Genes Genetic Genetic Transcription Goals Health Heterochromatin Histones Hyperoxia Hypersensitivity Immune response Infection Inflammation Influenza A virus Inherited Knockout Mice Label Laboratories Life Lung Lung diseases Modeling Mus Neonatal Hyperoxic Injury Oxidative Stress Oxygen Pathogenesis Pathogenicity Positioning Attribute Premature Infant Proliferating Proliferation Marker Proteins Public Health Pulmonary Fibrosis Recombinants Reporter Research Risk Severities Shapes Structure Testing Virus Diseases cell injury chromatin immunoprecipitation daughter cell experience fetal genetic information genotoxicity improved lung development model design mouse model next generation novel novel therapeutics oxidative damage postnatal prenatal self-renewal therapy design therapy design/development transcriptome sequencing tumor progression

项目摘要

PROJECT SUMMARY (ABSTRACT) There is growing appreciation that prenatal and postnatal environmental factors shape our health later in life. One of the most profound environmental factors that the developing lung will ever experience is oxygen as it transitions at birth from a fetal to air environment. While the term lung is prepared to breathe oxygen, the preterm lung transitions into air too soon and is often exposed to excess oxygen used to maintain appropriate oxygen saturations. This aberrant oxygen exposure at birth increases the risk for long-term lung disease through poorly understood mechanisms. Our laboratory developed and uses a unique mouse model designed to understand how high levels of oxygen at birth increases the severity of influenza A virus (IAV) infections in adults. Studies conducted during the previous funding period established that neonatal hyperoxia accelerates proliferation of alveolar epithelial type 2 cells (AEC2s), that these cells are slowly depleted when mice return to room air, and that the loss of AEC2s contributes to fibrotic lung disease when the mice are infected with IAV. This proposal builds on these findings by investigating how the oxygen-dependent depletion of AEC2s enhances the severity of IAV infections. Using genetic lineage studies, we found that neonatal hyperoxia depletes AEC2s by stimulating their differentiation into alveolar epithelial type 1 cells (AEC1s), neonatal hyperoxia enhances death of AEC1s during IAV infection, and that many AEC1s in adult mice exposed to neonatal hyperoxia express Ki67, a proliferation marker traditionally used to mark cancer progression. Recent studies however show Ki67 does not regulate cell proliferation but rather modifies gene expression via its ability to organize heterochromatin. Because proliferating cells are hypersensitive to the genotoxic effects of hyperoxia and damaged cells can transmit that experience thorough epigenetic inheritance, we will test the hypothesis that neonatal hyperoxia enhances sensitivity to IAV infection by inducing Ki67-dependent epigenetic changes in proliferating AEC2s that are maintained when they differentiate into AEC1s. Aim 1 uses novel Ki67-reporter and Ki67-null mice to determine whether AEC2s that proliferate during neonatal hyperoxia produce AEC1s that are marked by persistent Ki67 expression. Aim 2 infects these mice with recombinant strains of IAV-expressing fluorescent protein used to determine whether Ki67 modifies how AEC1s respond to IAV infection. Aim 3 uses cell-specific deep RNA sequencing and chromatin immunoprecipitation to determine whether Ki67 modifies a subset of oxygen-dependent changes in gene expression and that these changes help explain why AEC1s are susceptible to IAV infection. Understanding how neonatal hyperoxia shapes how AECs respond to IAV infection in mice is important because the scientific discoveries will stimulate development of therapies designed to improve the health of people born preterm.

项目总结（摘要）