The Involvement of PBRM1 in Alveolar Macrophage Development, Homeostasis, and Immune Function

PBRM1 参与肺泡巨噬细胞发育、稳态和免疫功能

• 批准号: 10605100
• 负责人: HANNAH Caroline RATTU MANDIAS
• 金额: $ 4万
• 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: 2023-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605100
• 关键词: ATAC-seq; Address; Adoptive Transfer; Affect; Alveolar; Alveolar Macrophages; Anti-Inflammatory Agents; Apoptotic; Asthma; Binding; Biological Assay; Blood-Air Barrier; Bone Marrow; Cause of Death; Cells; Cessation of life; Chimera organism; Chromatin; Chromatin Remodeling Factor; Chronic; Chronic Obstructive Pulmonary Disease; Communication; Complex; Cues; DNA; DNA Methylation; Data; Development; Disease; Elderly; Environment; Epigenetic Process; Epithelium; Exhibits; Family; Functional disorder; Future; Gene Expression; Gene Expression Profile; Generations; Genetic; Genetic Transcription; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Hematopoietic; Homeostasis; Host Defense; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunocompromised Host; Individual; Inflammatory; Inflammatory Response; Influenza; Knock-out; Longitudinal Studies; Lung; Lung diseases; Lung infections; Macrophage; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Microbe; Mission; Modeling; Modification; Molecular; Mononuclear; Morbidity - disease rate; Mus; Myelogenous; PPAR gamma; Pathway interactions; Phagocytes; Phagocytosis; Phenotype; Physiological; Play; Pneumonia; Population; Process; Property; Pulmonary alveolar structure; Research; Research Proposals; Respiratory Tract Infections; Role; Sentinel; Signal Transduction; Signaling Molecule; Stimulus; Stress; Structure of parenchyma of lung; T-Cell Activation; T-Lymphocyte; Tissues; Toxin; Transforming Growth Factor beta; United States National Institutes of Health; Variant; Viral; Virus Diseases; adaptive immunity; chromatin remodeling; cofactor; cytokine; epigenetic therapy; fetal; immune function; improved; in vivo; influenza infection; intercellular communication; monocyte; mortality; mouse model; novel; pathogen; prevent; programs; pulmonary function; recruit; response; self-renewal; surfactant; targeted treatment; tissue repair; transcription factor; transcriptome sequencing

PROJECT SUMMARY Pulmonary disorders like respiratory infections are one of the leading causes of death in the world and result in millions of deaths annually. The immune system’s initial line of defense against lung disease are mononuclear phagocytes called alveolar macrophages (AMs). These immune sentinels play an important role during homeostasis by clearing foreign pathogens like microbes and toxins in the airways of the lungs via phagocytosis. Additionally, AMs have an active role in pulmonary tissue repair by conducting efferocytosis, a type of phagocytosis that specifically removes apoptotic cells. By preventing the release of proinflammatory cytokines while secreting anti-inflammatory signals during efferocytosis, AMs contribute to barrier immunity and exhibit an immunosuppressive phenotype. Studies have also demonstrated that AMs communicate intercellularly with epithelial and T cells to prevent unneeded proinflammatory responses. Research into AM development has shown that tissue-specific cytokines derived from the lungs, such as GM-CSF and TGF-β, are required for the differentiation of monocytes into mature AMs. This plastic response to the pulmonary microenvironment is regulated by epigenetic modifications, such as DNA methylation and transcription factor recruitment. Notably, aberrant AM development and function have been implicated in the progression of multiple lung malignancies, such as influenza infections, chronic obstructive pulmonary disease, and some types of lung cancer. Furthermore, dysfunctional AMs can contribute to the increased morbidity and mortality of elderly and immuno-compromised individuals. As such, this study’s long-term goal to enhance the understanding of epigenetic mechanisms governing AM development and function tightly aligns with NIH’s mission to prevent disease and improve human health. The key focus of this project aims to investigate the role of PBRM1, the defining subunit of the SWI/SNF family PBAF complex, in dictating the development and function of murine AMs. To elucidate the effects of PBRM1-deletion on AM development and phenotype, I plan to 1) determine the requirement for PBRM1 in AM development and self-renewal, 2) determine the role of PBRM1 in transcriptional and epigenetic programs of AMs by performing RNA-seq and ATAC-seq on PBRM1 WT and KO AMs to identify pathways and transcription factors which may be dependent on PBRM1, as well as overlapping this data with CUT&RUN data of PBRM1 and transcription factors known to drive AM development, such as PPARγ and PU.1.; and 3) determine the functional effects of myeloid-specific PBRM1 deletion during influenza infection. These studies will assess the epigenetic and transcriptional effects of PBRM1-loss in AMs and provide evidence for novel co-regulators of PBRM1. In the future, this research will serve to inform the development of targeted therapies of PBRM1-dependent processes affecting lung disease.

项目摘要 肺部疾病如呼吸道感染是世界上主要的死亡原因之一， 每年有数百万人死亡。免疫系统抵御肺部疾病的最初防线是单核细胞 称为肺泡巨噬细胞（AM）的吞噬细胞。这些免疫哨兵发挥重要作用， 通过清除肺部气道中的外来病原体，如微生物和毒素， 吞噬作用此外，AM通过传导巨噬细胞增多， 一种专门清除凋亡细胞的吞噬作用。通过阻止促炎因子的释放 细胞因子，同时在巨噬细胞增多症期间分泌抗炎信号，AM有助于屏障免疫， 表现出免疫抑制表型。研究还表明， 与上皮细胞和T细胞细胞的细胞间结合，以防止不必要的促炎反应。研究AM 研究表明，来源于肺的组织特异性细胞因子，如GM-CSF和TGF-β， 是单核细胞分化为成熟AM所必需的。这种对肺部的可塑性反应 微环境受表观遗传修饰的调节，如DNA甲基化和转录因子 招聘值得注意的是，异常的AM发育和功能已经涉及到肿瘤的进展。 多发性肺部恶性肿瘤，如流感感染、慢性阻塞性肺疾病和一些 肺癌的早期症状此外，功能失调的AM可导致以下疾病的发病率和死亡率增加： 老年人和免疫功能低下的人。因此，本研究的长期目标是提高 对管理AM发育和功能的表观遗传机制的理解与NIH的 预防疾病和改善人类健康的使命。该项目的重点是调查 PBRM 1是SWI/SNF家族PBAF复合物的定义亚基，它在决定发育和 小鼠AM的功能。为了阐明PBRM 1缺失对AM发育和表型的影响，我计划 1）确定在AM开发和自我更新中对PBRM 1的要求，2）确定 通过对PBRM 1进行RNA-seq和ATAC-seq，PBRM 1在AM的转录和表观遗传程序中的作用 WT和KO AM以鉴定可能依赖于PBRM 1的途径和转录因子，以及 将该数据与PBRM 1和已知驱动AM的转录因子的CUT&RUN数据重叠 发育，如PPARγ和PU.1.;和3）确定骨髓特异性PBRM 1的功能作用 流感病毒感染期间的缺失。这些研究将评估表观遗传和转录的影响， PBRM 1-AM中的损失，并为PBRM 1的新型共调节剂提供证据。在未来，这项研究将 有助于为影响肺部疾病的PBRM 1依赖性过程的靶向疗法的开发提供信息。