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 医疗的进步使早产婴儿的数量越来越多。但是， 早期妊娠年龄的生存增加伴随着发病率的增加。支气管肺 发育不良（BPD）是最普遍的早产主要并发症，至少有四分之一 出生体重小于1500克的婴儿。令人震惊的是，BPD的速率正在增加，而比率 早产的其他几种院内并发症也下降了。 BPD倾向于过早婴儿 在新生儿周期和出院后，较高的死亡率和发病率风险均形成 新生儿重症监护室。许多早产的幸存者将继续具有持续的呼吸道 症状和肺功能降低到成年。除了呼吸并发症外，BPD也是 神经发育障碍的最强预测指标之一。这些BPD的终身并发症 产生巨大的健康负担，并需要广泛的医疗保健利用。目前，没有 BPD的有效治疗。该疾病的关键致病机制尚未完全了解，并且 因此，我们缺乏开发新疗法的明确途径。在 BPD的发病机理是氧气给药，用作早产过早后的挽救生命干预措施。 未成熟肺暴露于氧气水平增加会导致深刻的炎症反应 永久破坏正常的肺发育。但是，并非每个过早的婴儿都对 氧诱导的损伤。因此，识别导致氧气的细胞和分子机制 诱发的炎症和个体敏感性的差异有可能建立新的治疗性 目标。我建议以最新的概念，技术和计算的进步来识别先天性 启动和维持BPD病理炎症反应的免疫细胞。识别 与疾病相关的细胞，我将应用最先进的测序技术来研究其基因表达和 调节基因表达的表观遗传机制。使用计算分析我将集成 遗传和表观遗传数据以识别可能驱动BPD病理学的候选基因 在疾病易感性方面造成个体差异。了解基因的基本生物学 在发育中肺中先天免疫细胞中的表达和调节不仅会使早产儿受益 使用BPD，但可以在其他几种呼吸系统疾病中用于治疗目的。

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