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，是早产的最常见主要并发症出生影响至少四分之一的婴儿出生体重小于1500克。许多早产儿 BPD将继续具有持续的呼吸道症状，并将肺功能降低到成年期。这些 BPD的终身并发症造成了巨大的健康负担，并需要广泛的医疗保健利用。目前，BPD没有有效的预防或个性化治疗方法。并非每个早产儿开发BPD，BPD易感性的这种个体变异性可能通过复杂的相互作用来解释在环境，细胞，遗传和表观遗传因素之间。补充氧气给药在新生儿时期，救生仍然是BPD病理生理学的关键决定因素。未成熟的暴露肺部氧气水平升高会引起炎症反应，导致异常肺发育。但是，肺免疫细胞，特别是与先天免疫反应有关的肺部细胞及其尚不完全了解伴随的基因表达程序来保护BPD。这该建议的总体目的是识别和表征特定的肺髓样细胞及其基因为氧诱导的肺损伤提供保护的程序。我们的假设是先天免疫在肺中激活的反应与发展为BPD的早产儿和弹性的反应不同疾病。基于我们的新颖发现，触发受体的遗传丧失在髓样中表达的受体的功能丧失细胞2（TREM2）在高氧诱导的肺损伤中具有保护性，我们提出抑制trem2信号传导可以利用以调节先天免疫反应以防止异常的肺发育。在目标1中我们将采用单细胞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AIM 2中，我们将使用髓样暴露于新生儿高氧和使用Atacseq和Atacseq和 Chipseq确定TREM2在A上指导致病性免疫反应的调节机制转录级别。最后，为治疗靶向的翻译潜力建立原理证明 of trem2我们将测试trem2阻断体内的抗体，并评估房间空气中的高氧恢复（AIM 3）。进一步研究小鼠与人之间基因调节途径的保护使用这些基因途径来开发靶向疗法的声音原理。这个项目将确定独特的肺髓样细胞的基因调节网络，支持在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弹性的新型途径，这将告知多因素BPD的更有针对性管理的发展。