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

点击翻译按钮获取中文摘要

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.