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Let-7b in BPD

BPD 中的 Let-7b

基本信息

批准号：
10655734
负责人：
Namasivayam Ambalavanan
金额：
$ 55.44万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-14 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655734
关键词：
Adult Age Alveolar Angiogenesis Inhibition Attenuated Basic Science Biological Markers Birth Blood Blood Vessels Bronchopulmonary Dysplasia Cell Culture System Cell Culture Techniques Cessation of life Clinical Development Disease Progression Early identification Epithelial Cells Extremely Low Birth Weight Infant Fetal Lung Functional disorder Genomics Human Hyperoxia Impairment Incidence Infant Lung Lung diseases Measures Mechanics Mediator Messenger RNA Metagenomics MicroRNAs Mitochondria Modeling Monitor Morbidity - disease rate Mus NF-kappa B Newborn Infant Oxidative Stress Oxygen Phenotype Plasma Premature Infant Prospective cohort Proteomics Pulmonary Fibrosis Pulmonary Hypertension Research Risk Role Sampling Severity of illness Signal Transduction Small RNA Source Staging Structure of parenchyma of lung Testing Time Trachea Transgenic Mice Urine Vascular remodeling airway epithelium angiogenesis aspirate biomarker identification cohort cytokine exome sequencing extreme prematurity genome wide association study improved inhibitor lung development metabolomics microbial microbiome microbiome research mouse model normoxia novel novel therapeutic intervention overexpression postnatal prospective pulmonary function respiratory transcriptome sequencing transcriptomics treatment response

项目摘要

Project Summary Bronchopulmonary dysplasia (BPD) is common in extremely low birth weight (ELBW) infants. Recently, we discovered that the strongest biomarker signal was of microRNA let-7b-5p, with a 46-fold increase (p<0.001) at birth in the blood of infants who subsequently developed severe BPD (versus no BPD) many weeks later at 36w post-menstrual age. We also found a 14-fold increase of let-7b-5p on day 1 in the tracheal aspirate of infants who subsequently developed BPD. In cell culture, airway epithelial cells were the primary source of let-7b-5p, that increased with hyperoxia. We found that excessive let-7b inhibits angiogenesis, and that let-7b inhibition during hyperoxia improves lung development in newborn mice. In the “Let-7b in BPD” project, we will build upon our exciting discovery of let-7b-5p as a robust biomarker of BPD, and determine its relevance to lung development and BPD. We will test the central hypotheses that miRNA let-7b-5p is (a) a valuable biomarker for staging, monitoring disease progression and response to therapy, (b) is released from airway epithelial cells by oxidative stress, (c) is a contributor to dysregulated angiogenesis in bronchopulmonary dysplasia, and (d) that inhibition of let-7b signaling improves lung angiogenesis and attenuates the BPD phenotype. We will test the hypotheses by the following Specific Aims: Specific Aim 1 – Determine if plasma let-7b-5p concentrations in extremely preterm infants track with lung disease progression and correlate with response to therapy. Let-7b-5p will be measured in serial plasma samples from a well characterized prospective cohort of 150 extremely preterm infants. We will define the temporal changes in let-7b-5p with respiratory illness severity, BPD staging and lung mechanics at 36w PMA, and with clinical therapies. Specific Aim 2 – Determine the mechanisms of Let-7b release by newborn mouse lung airway epithelium To confirm that the let-7b-5p release by oxidative stress is the key upstream mechanism, we will use novel transgenic mice. We will test the hypothesis that reduction of mitochondrial ROS reduces let-7b-5p and the BPD phenotype, and determine the role of Nrf2 and NF-kB signaling using specific inhibitors/modulators in cell culture models. Specific Aim 3 – Determine effects of excessive let-7b-5p signaling on lung microvascular development. We will test the hypothesis that over-expression of let-7b-5p induces impaired lung microvascular development, inducing a BPD phenotype in newborn mice even in normoxia, and that inhibition of let-7b-5p improves lung development in hyperoxia- exposed newborn mouse lung (BPD model).

项目总结