Role of neonatal lung macrophages in mediating resilience to hyperoxia induced lung injury via TREM2 signaling

新生儿肺巨噬细胞通过 TREM2 信号传导介导高氧诱导肺损伤的恢复能力

基本信息

批准号：
10720557
负责人：
Eniko Sajti
金额：
$ 77.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10720557
关键词：
ATAC-seq Adult Affect Age Air Alveolar Macrophages Apoptosis Arbitration Architecture Binding Birth Weight Blocking Antibodies Bronchopulmonary Dysplasia Cells ChIP-seq Chromatin Chronic lung disease Complex Complication Cre-LoxP DNA Data Development Disease Disease susceptibility Enhancers Environment Epigenetic Process Epithelial Cells Exposure to Extremely Low Birth Weight Infant Functional disorder Gene Expression Genes Genetic Genetic Transcription Goals Harvest Health Histology Histone Acetylation Human Hyperoxia Immune Immune response Individual Infant Inflammatory Inflammatory Response Injury Innate Immune Response Innate Immune System Intervention Intrinsic factor Investigation Life Lung Macrophage Measures Mediating Modeling Modification Mouse Strains Mus Myelogenous Myeloid Cells Neonatal Neonatal Hyperoxic Injury Outcome Oxygen Oxygen Therapy Care Pathogenicity Pathway interactions Patients Play Predisposition Premature Birth Premature Infant Prevention Pulmonary Pathology Randomized Recovery Regulator Genes Regulatory Pathway Reporting Resistance Respiratory Signs and Symptoms Role Severities Signal Induction Signal Pathway Signal Transduction Sorting Stimulus Supporting Cell Survivors TP53 gene TREM2 gene Testing Tissues Uterus Wild Type Mouse Work body system cell injury cell type epigenomics gene conservation gene regulatory network health care service utilization hyperoxia induced lung injury in vivo individual variation inhibiting antibody innate immune mechanisms insight interstitial loss of function lung development lung injury lung regeneration lung repair monocyte neonatal mice neonatal period new therapeutic target novel novel strategies personalized medicine premature preservation prevent programs pulmonary function receptor regenerative repaired resilience respiratory health response single-cell RNA sequencing sound targeted treatment therapeutic target therapy design tissue injury tissue regeneration transcription factor transcriptome transcriptome sequencing transcriptomics translational potential

项目摘要

ABSTRACT/PROJECT SUMMARY Bronchopulmonary dysplasia (BPD), a chronic lung disease, is the most common major complication of preterm birth affecting at least one fourth of infants born with a birth weight less than 1500g. Many premature infants with BPD will continue to have persistent respiratory symptoms and decreased lung function into adulthood. These life-long complications of BPD create significant health burden and necessitate extensive health care utilization. Currently, there is no effective prevention or personalized treatment for BPD. Not every premature infant develops BPD, and this individual variability in BPD susceptibility is likely explained by complex interactions between environmental, cellular, genetic, and epigenetic factors. Supplemental oxygen administration, while lifesaving in the neonatal period, remains a key determinant of BPD pathophysiology. Exposure of the immature lung to increased levels of oxygen elicits an inflammatory response resulting in abnormal lung development. However, the lung immune cells, specifically those involved in the innate immune response, and their accompanying gene expression programs that provide protection against BPD are not completely known. The overall objective of this proposal is to identify and characterize specific lung myeloid cells and their gene programs that provide protection to oxygen-induced lung injury. Our hypothesis is that the innate immune response activated in the lung differs between premature infants who develop BPD and those that are resilient to disease. Based on our novel finding that genetic loss of function of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is protective in hyperoxia-induced lung injury, we propose that inhibition of TREM2 signaling may be exploited to modulate the innate immune response to prevent abnormal lung development. In Aim 1 we will employ single cell RNAseq and TREM2-deficient mice to define how TREM2 regulates gene expression and severity of lung injury after neonatal hyperoxia exposure. In Aim 2 we will apply novel approaches using myeloid p53-deficient mice exposed to neonatal hyperoxia and interrogate epigenomic modifications using ATACseq and ChIPseq to identify the regulatory mechanisms by which TREM2 directs a pathogenic immune response on a transcriptional level. Lastly, to establish proof-of-principle for the translational potential of therapeutic targeting of TREM2 we will test a TREM2 blocking antibody in vivo and assess recovery from hyperoxia in room air (Aim 3). Further investigations of the conservation of gene regulatory pathways between mice and humans will provide a sound rationale to use these gene pathways to develop targeted therapies. This project will identify unique gene regulatory networks of lung myeloid cells that support a regenerative immune response in the developing lung. These findings will elucidate novel pathways of neonatal lung resilience after hyperoxia, which will inform the development of more targeted management of multifactorial BPD.

摘要/项目摘要支气管肺发育不良（BPD）是一种慢性肺部疾病，是早产儿最常见的主要并发症至少四分之一的出生体重低于 1500 克的婴儿受到影响。许多早产儿患有 BPD 到成年后仍会持续出现呼吸道症状和肺功能下降。这些 BPD 的终生并发症会造成严重的健康负担，需要广泛的医疗保健利用。目前，BPD尚无有效的预防或个性化治疗方法。并不是每个早产儿发展 BPD，而 BPD 易感性的个体差异可能是通过复杂的相互作用来解释的环境、细胞、遗传和表观遗传因素之间的关系。补充氧气的同时挽救新生儿期的生命，仍然是 BPD 病理生理学的关键决定因素。暴露不成熟的一面肺部氧气含量增加会引发炎症反应，导致肺部发育异常。然而，肺免疫细胞，特别是那些参与先天免疫反应的细胞，及其提供针对 BPD 保护的伴随基因表达程序尚不完全清楚。这该提案的总体目标是识别和表征特定的肺骨髓细胞及其基因为氧引起的肺损伤提供保护的计划。我们的假设是先天免疫患有 BPD 的早产儿和有弹性的早产儿之间，肺部激活的反应有所不同到疾病。基于我们的新发现，即骨髓表达的触发受体功能的遗传丧失 cells 2 (TREM2) 在高氧诱导的肺损伤中具有保护作用，我们认为抑制 TREM2 信号传导可用于调节先天免疫反应，以防止肺部发育异常。在目标 1 中，我们将使用单细胞 RNAseq 和 TREM2 缺陷小鼠来定义 TREM2 如何调节基因表达和新生儿高氧暴露后肺损伤的严重程度。在目标 2 中，我们将应用利用骨髓细胞的新方法 p53 缺陷小鼠暴露于新生儿高氧并使用 ATACseq 和询问表观基因组修饰 ChIPseq 用于识别 TREM2 指导致病性免疫反应的调节机制转录水平。最后，为治疗靶向的转化潜力建立原理验证对于 TREM2，我们将在体内测试 TREM2 阻断抗体，并评估室内空气中高氧血症的恢复情况（目标 3）。对小鼠和人类之间基因调控途径保守性的进一步研究将提供使用这些基因途径开发靶向疗法的合理理由。该项目将确定独特的肺骨髓细胞的基因调控网络支持发育中的再生免疫反应肺。这些发现将阐明高氧后新生儿肺恢复能力的新途径，从而为新生儿提供信息开发更有针对性的多因素 BPD 管理。