Epigenomics of mononuclear phagocytes in prematurity associated lung disease

项目总结/摘要 医学的进步使越来越多的早产儿得以存活。但 早期胎龄存活率的增加伴随着发病率的增加。支气管 发育不良（BPD）是早产最常见的主要并发症，影响至少四分之一的 出生体重低于1500克的婴儿。令人担忧的是，BPD的比率正在增加，而 其他几种早产住院并发症也有所下降。BPD易使早产儿 新生儿期以及出院后的死亡率和发病率风险较高， 新生儿重症监护室许多早产的幸存者将继续有持续的呼吸道感染， 症状和肺功能下降到成年。除了呼吸系统并发症，BPD还 是神经发育障碍最强的预测指标之一BPD的这些终生并发症 造成严重的健康负担，并需要广泛的卫生保健利用。目前尚无 有效治疗BPD。该疾病的关键致病机制尚未完全了解， 因此，我们缺乏开发新疗法的明确途径。一个因素，发挥了核心作用， BPD的发病机制是氧气管理，用作早产后的救生干预。 未成熟的肺暴露于增加的氧气水平会导致严重的炎症反应， 永久性地破坏了正常的肺发育。然而，并不是每个早产儿都同样敏感。 氧致损伤因此，确定导致氧气的细胞和分子机制， 诱导的炎症和个体易感性的差异有可能建立新的治疗方法， 目标的我建议建立在最近的概念，技术和计算的进步，以确定先天的 启动和维持BPD中病理性炎症反应的免疫细胞。在确定了 疾病相关细胞，我将应用最先进的测序技术来研究它们的基因表达， 调节基因表达的表观遗传机制。使用计算分析，我将整合 遗传和表观遗传数据，以确定可能驱动BPD病理的候选基因， 有助于疾病易感性的个体差异。了解基因的基础生物学 在发育中的肺中先天免疫细胞的表达和调节不仅有益于早产儿， BPD，但可以用于治疗其他几种呼吸道疾病。

PROJECT SUMMARY/ABSTRACT Medical advances have made it possible for premature infants to survive in increasing numbers. However, the increased survival at early gestational ages is accompanied with increased morbidity. Bronchopulmonary dysplasia (BPD) is the most prevalent major complication of premature birth affecting at least one quarter of infants born with a birth weight less than 1500g. Alarmingly, the rate of BPD is increasing, while rates of several other in-hospital complications of premature birth have dropped. BPD predisposes premature infants to a higher mortality and morbidity risk both in the immediate neonatal period as well as after discharge form the neonatal intensive care unit. Many survivors of premature birth will continue to have persistent respiratory symptoms and decreased lung function into adulthood. In addition to the respiratory complications, BPD is also one of the strongest predictors of neurodevelopmental impairment. These life-long complications of BPD create significant health burden and necessitate extensive health care utilization. Currently, there is no effective treatment for BPD. Key pathogenic mechanisms of the disease are not completely understood and therefore we lack a clear path for development of new therapies. One factor that plays a central role in the pathogenesis of BPD is oxygen administration, used as a life-saving intervention after premature birth. Exposure of the immature lung to increased levels of oxygen results in a profound inflammatory response that permanently disrupts normal lung development. However, not every premature infant is equally sensitive to oxygen-induced injury. Therefore, identifying the cellular and molecular mechanisms leading to oxygen induced inflammation and variance in individual susceptibility has the potential to establish new therapeutic targets. I propose to build on recent conceptual, technical and computational advances to identify the innate immune cells that initiate and maintain the pathologic inflammatory response in BPD. After identifying the disease-relevant cells, I will apply state of the art sequencing techniques to study their gene expression and the epigenetic mechanisms that regulate gene expression. Using computational analysis I will integrate the genetic and epigenetic data to identify candidate genes that are likely to drive the pathology in BPD and contribute to individual differences in disease susceptibility. Understanding the fundamental biology of gene expression and regulation in innate immune cells in the developing lung will not only benefit premature infants with BPD, but could be harnessed for therapeutic purposes in several other respiratory diseases.