Epigenomics of mononuclear phagocytes in prematurity associated lung disease

早产儿相关肺部疾病中单核吞噬细胞的表观基因组学

• 批准号: 10339358
• 负责人: Eniko Sajti
• 金额: $ 17.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10339358
• 关键词: Adult; Affect; Air; Alveolar Macrophages; Bioinformatics; Biological Assay; Biology; Birth Weight; Blood; Bronchopulmonary Dysplasia; C57BL/6 Mouse; Candidate Disease Gene; Cells; Chromatin; Complication; Computer Analysis; Data; Dendritic Cells; Development; Disease; Disease susceptibility; Drops; Epigenetic Process; Exposure to; Fluorescence-Activated Cell Sorting; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genome; Genomics; Gestational Age; Health; Hospitalization; Hospitals; Hyperoxia; Immune; Individual; Individual Differences; Infant; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Laboratories; Lead; Life; Lung; Lung diseases; Measures; Medical; Modification; Molecular; Mononuclear; Morbidity - disease rate; Mouse Strains; Mus; Natural Immunity; Neonatal; Neonatal Hyperoxic Injury; Neonatal Intensive Care Units; Neurodevelopmental Impairment; Oxygen; Oxygen Therapy Care; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Phagocytes; Phenotype; Play; Predisposition; Premature Birth; Premature Infant; Prevention; Resistance; Resources; Respiratory Disease; Respiratory Signs and Symptoms; Risk; Role; Savings; Severity of illness; Signal Pathway; Survivors; Techniques; Testing; Therapeutic; Tissues; Transposase; cell type; cytokine; differential expression; effective therapy; environmental stressor; epigenomics; experience; gene environment interaction; gene regulatory network; health care service utilization; improved; innovation; insight; interstitial; lung development; lung injury; macrophage; monocyte; mortality; neonatal care; neonatal period; new therapeutic target; next generation sequencing; novel; novel strategies; novel therapeutics; postnatal; postnatal development; postnatal period; premature; premature lungs; programs; pulmonary function; resilience; respiratory; response; tissue injury; transcription factor; transcriptome; transcriptomics

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.

项目摘要/摘要 医学的进步使早产儿存活的人数越来越多。然而， 早期妊娠存活率的增加伴随着发病率的增加。支气管肺 发育不良(BPD)是早产最常见的主要并发症，影响到至少四分之一的 出生体重低于1500克的婴儿。令人震惊的是，石油日产量正在增加，而石油日产量 早产的其他几个住院并发症已经下降。BPD使早产儿容易患上 新生儿出生初期和出院后死亡率和发病风险均较高。 新生儿重症监护室。许多早产幸存者将继续患有持续呼吸道疾病 症状和肺功能下降一直持续到成年。除了呼吸道并发症外，BPD还 神经发育障碍的最强预测指标之一。BPD的这些终生并发症 造成巨大的健康负担，并需要广泛利用卫生保健。目前，没有 对BPD的有效治疗。该病的主要致病机制尚不完全清楚， 因此，我们缺乏一条开发新疗法的明确途径。发挥核心作用的一个因素是 BPD的发病机制是给氧，用于早产后的救命干预。 将未成熟的肺暴露在氧气水平增加会导致深刻的炎症反应， 会永久性地破坏正常的肺部发育。然而，并不是每个早产儿都同样对 氧气引起的损伤。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。我建议在最近的概念、技术和计算进展的基础上，确定先天的 启动和维持BPD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和 调控基因表达的表观遗传机制。使用计算分析，我将积分 遗传学和表观遗传学数据，以确定可能驱动BPD和BPD病理的候选基因 导致疾病易感性的个体差异。了解基因的基本生物学 发育中的肺中先天免疫细胞的表达和调节不仅有利于早产儿 BPD，但可用于治疗其他几种呼吸系统疾病。

项目成果

Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes.

• DOI: 10.7554/elife.62522
• 发表时间: 2020-11-09
• 期刊: eLife
• 影响因子: 7.7
• 作者: Wang A;Chiou J;Poirion OB;Buchanan J;Valdez MJ;Verheyden JM;Hou X;Kudtarkar P;Narendra S;Newsome JM;Guo M;Faddah DA;Zhang K;Young RE;Barr J;Sajti E;Misra R;Huyck H;Rogers L;Poole C;Whitsett JA;Pryhuber G;Xu Y;Gaulton KJ;Preissl S;Sun X;NHLBI LungMap Consortium
• 通讯作者: NHLBI LungMap Consortium