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

• 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
• 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

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。 出生体重低于1500克的婴儿中，至少有四分之一的出生会受到影响。许多早产儿患有 BPD将继续有持续的呼吸道症状和肺功能下降，直到成年。这些 BPD的终生并发症造成了巨大的健康负担，需要广泛的医疗保健。 目前，对BPD没有有效的预防或个体化治疗。并不是每个早产儿 发展成bpd，这种bpd易感性的个体差异很可能是由复杂的相互作用解释的。 在环境、细胞、遗传和表观遗传因素之间。补充氧气，同时 在新生儿期挽救生命，仍然是BPD病理生理学的关键决定因素。暴露不成熟的人 肺内氧气水平升高会引起炎症反应，导致肺发育异常。 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 提供对BPD的保护的伴随的基因表达程序并不完全清楚。这个 这项建议的总体目标是鉴定和表征特定的肺髓系细胞及其基因 为氧气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的早产儿和有恢复力的早产儿在肺中激活的反应不同 为了疾病。基于我们的新发现，在髓系上表达的触发受体功能的遗传丧失 细胞2(TREM2)在高氧性肺损伤中具有保护作用，我们认为抑制TREM2信号转导 可能被用来调节先天免疫反应，以防止肺发育异常。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，我们将应用使用髓系的新方法 P53基因缺陷小鼠暴露于新生高氧中，并使用ATACseq和ATACseq询问表观基因组修饰 ChIPseq以确定TREM2通过其引导致病免疫反应的调节机制 转录水平。最后，为治疗靶向的翻译潜力建立原则证明 对于TREM2，我们将在体内测试TREM2封闭抗体，并评估从室内空气中的高氧中恢复(AIM 3)。进一步研究老鼠和人类之间的基因调控通路的保守性将提供 有充分的理由利用这些基因途径来开发靶向治疗。该项目将确定独特的 肺髓系细胞在发育过程中支持再生免疫反应的基因调控网络 阿龙。这些发现将阐明高氧后新生儿肺弹性的新途径，这将为 制定更有针对性的多因素bpd管理。