Let-7b in BPD

BPD 中的 Let-7b

• 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
• 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

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).

项目概要 支气管肺发育不良（BPD）在极低出生体重（ELBW）婴儿中很常见。 最近，我们发现最强的生物标志物信号是 microRNA let-7b-5p，其信号强度是 microRNA let-7b-5p 的 46 倍。 随后出现严重 BPD 的婴儿出生时血液中的浓度增加 (p<0.001) 没有 BPD）许多周后，在月经后 36 周时，我们还发现当天的 let-7b-5p 增加了 14 倍。 随后患 BPD 的婴儿气管抽吸物中的 1 细胞培养物中的气道上皮细胞。 是let-7b-5p的主要来源，随着高氧血症的增加，我们发现过量的let-7b会抑制。 血管生成，高氧期间的 let-7b 抑制可改善新生小鼠的肺部发育。 在“BPD 中的 Let-7b”项目中，我们将基于 let-7b-5p 的令人兴奋的发现作为一个强大的 BPD 的生物标志物，并确定其与肺部发育和 BPD 的相关性。 假设 miRNA let-7b-5p 是 (a) 一种用于分期、监测疾病的有价值的生物标志物 进展和对治疗的反应，（b）通过氧化应激从气道上皮细胞释放， (c) 是支气管肺发育不良中血管生成失调的一个因素，并且 (d) 抑制 let-7b 信号传导可改善肺血管生成并减弱 BPD 表型。 我们将通过以下具体目标来检验假设： 具体目标 1 – 确定极早产儿的血浆 let-7b-5p 浓度是否与肺部一致 疾病进展并与治疗反应相关。 Let-7b-5p 将在一系列血浆样本中进行测量，这些血浆样本来自一组经过充分表征的前瞻性队列。 我们将定义 150 名患有呼吸道疾病的极早产儿的 let-7b-5p 的时间变化。 严重程度、BPD 分期和 36 周 PMA 时的肺力学，以及临床治疗。 具体目标 2 – 确定新生小鼠肺气道上皮释放 Let-7b 的机制 为了确认氧化应激释放的let-7b-5p是关键的上游机制，我们将使用 我们将测试线粒体 ROS 减少会减少 let-7b-5p 的假设。 和 BPD 表型，并使用特定的方法确定 Nrf2 和 NF-kB 信号传导的作用 细胞培养模型中的抑制剂/调节剂。 具体目标 3 – 确定过量的 let-7b-5p 信号传导对肺微血管发育的影响。 我们将检验 let-7b-5p 过度表达会导致肺微血管受损的假设 发育，即使在常氧条件下也会在新生小鼠中诱导 BPD 表型，并且抑制 let-7b-5p 改善高氧暴露的新生小鼠肺（BPD 模型）的肺发育。