Salivary miRNAs as Prognostic Markers of Pulmonary Hypertension Associated with Bronchopulmonary Dysplasia in Extremely Low Gestational Age Infants

项目摘要/摘要 随着新生儿护理的最新进展，极早产儿的存活率有所提高 出生体重非常低，尽管支气管肺发育不良(BPD)的并发症仍然存在。其中最 这些严重的并发症是肺动脉高压(BPD-PH)。早产儿BPD-PH的真实发生率 婴儿尚不清楚，但流行率估计在17%至40%之间。BPD和BPD-PH通常被诊断为 绝经后36周(PMA)。BPD-PH导致新生儿ICU天数增加， 呼吸机和氧气需求，以及气管切开和家用呼吸机支持的需要。此外， 这些婴儿的死亡率和发病率仍然很高，在他们出生的头两个月里，再次住院的人数增加了。 生命中的岁月。一些临床参数和定性标志物有助于预测36周BPD-PH的发展 胎膜早破，如小于胎龄儿、先兆子痫、绒毛膜羊膜炎和 在出生后7天和28天进行早期呼吸机支持。然而，我们缺乏定量的标记来预测 发展或长期结果，如死亡、再次住院或对治疗的反应。一种非侵入性 定量预测指标将有助于早期对这些婴儿进行分层，并适用于那些经常插管的婴儿 和医学上脆弱的婴儿。在我们对患有BPD-PH的婴儿的初步研究中，我们非侵入性地获得了 并确定了与低氧相关的一组特定的microRNAs(小的非编码RNA) 应激反应和血管生成途径。我们进一步进行了与气管相关的初步研究 用极早产儿的唾液样本抽吸样本。 在这个拟议的K23项目中，候选人(在一个杰出的多学科团队的建议下 Mentors)将研究极端早产儿的唾液样本，以早期识别 可以预测BPD-PH的发展及其长期预后。这将是一项针对婴儿的前瞻性研究 出生和怀孕28周；唾液样本将在7天和28天收集并分析标志物 这可以在怀孕36周时预测BPD-PH。候选人将评估婴儿的miRNA表达 在生命的第一年与BPD-PH进行比较，并根据他们的情况确定预测诊断和结果的标志物 超声心动图检查结果和需氧量。到本K23课程结束时，应聘者将学会如何 设计和开展未来的miRNA研究并分析其结果。她还将完成选择 相关课程是她临床研究硕士学位的一部分，并接受了职业指导 发展。数据将在会议上传播，并在同行评议的期刊上发表。总而言之，这是 项目将为未来的R01类型的应用提供一个强大的平台，并帮助延续候选人的积极 成为一名独立的内科科学家和国家认可的职业轨迹和最终目标 早产儿BPD-PH方面的专家。

PROJECT SUMMARY/ABSTRACT With recent advances in neonatal care, there is improved survival of extremely premature babies with very low birth weight, although the complications of bronchopulmonary dysplasia (BPD) remain. One of the most severe of these complications is pulmonary hypertension (BPD-PH). The true incidence of BPD-PH in preterm babies is unknown, but prevalence is estimated to range from 17-40%. BPD and BPD-PH are typically diagnosed at 36 weeks postmenstrual age (PMA). BPD-PH leads to more days in the neonatal ICU, increased days of ventilator and oxygen requirement, and the need for tracheostomy and home ventilator support. Furthermore, these infants continue to have high mortality and morbidity with increased hospital readmissions in their first 2 years of life. Some clinical parameters and qualitative markers help predict development of BPD-PH at 36 weeks PMA, such as infants born small for gestational age, maternal history of preeclampsia, chorioamnionitis, and early periods of ventilator support at 7 and 28 days of life. However, we lack quantitative markers to predict development or long-term outcomes such as death, re-hospitalization, or response to therapies. A non-invasive quantitative predictor would help stratify these infants early on and be appropriate for these frequently intubated and medically fragile infants. In our preliminary study among infants with BPD-PH, we non-invasively obtained tracheal aspirate and identified a specific panel of microRNAs (small noncoding RNAs) associated with hypoxic stress response and angiogenic pathways. We have further conducted preliminary studies correlating tracheal aspirate samples with that of saliva from extreme preterm infants. In this proposed K23 project, the Candidate (with advice from an outstanding multidisciplinary team of mentors) will study salivary samples of extreme preterm infants for early identification of target miRNAs that could predict development of BPD-PH and its long-term outcomes. This will be a prospective study of infants born <28 weeks of gestation; saliva samples will be collected at 7 and 28 days of age and analyzed for markers that could predict BPD-PH at 36 weeks of gestation. The Candidate will evaluate miRNA expression in infants with BPD-PH over the first year of life and identify markers that predict diagnosis and outcomes, based on their echocardiogram findings and oxygen requirements. By the end of this K23, the Candidate will have learned how to design and carry out future miRNA studies and analyze their results. She also will have completed selected relevant courses as part of her Master’s Degree in Clinical Research and received guidance on career development. Data will be disseminated at meetings and published in peer-reviewed journals. In summary, this project will provide a strong platform for future R01-type applications and help continue the Candidate’s positive career trajectory and ultimate goal to become an independent physician-scientist and nationally recognized expert in BPD-PH in premature infants.