Monocyte Production by Bone Marrow Progenitors

骨髓祖细胞产生单核细胞

基本信息

批准号：
9902323
负责人：
Helen S Goodridge
金额：
$ 42.5万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902323
关键词：
Blood Bone Marrow CPG-oligonucleotide Cells Clinical Cytoplasmic Granules DNA Dendritic Cells Development Emergency Situation Epigenetic Process Exhibits Expression Profiling GFI1 gene Gene Expression Gene Expression Profile Hematologist Homeostasis Host Defense Immune Immunity Immunologist Infection Inflammation Inflammatory Injections Interferons Interleukin-6 Intervention Leukocytes Lipopolysaccharides Malignant Neoplasms Modeling Modification Molecular Morphology Mus Myelogenous Myeloid Cells Myeloid Progenitor Cells Myelopoiesis Natural regeneration Pathology Pathway interactions Peripheral Peroxidases Population Production Property Proteins Reporting Role Route Shapes Sorting - Cell Movement Spleen Stimulus Stress Tissues antimicrobial cell type cytokine differential expression experimental study granulocyte-monocyte progenitors immunoregulation injured insight macrophage microbial monocyte neutrophil novel pathogen progenitor programs recruit repaired response stem cells tissue repair transcription factor translational approach tumor

项目摘要

PROJECT SUMMARY Monocytes are innate immune cells with diverse functions in host defense against infection and tumors, as well as tissue homeostasis, repair and regeneration. Monocytes perform surveillance roles in tissues throughout the body, and are stored in the bone marrow for rapid recruitment to infected or injured tissues. Two major classes of functionally distinct monocytes are found in the bone marrow, blood and spleen: classical (Ly6Chi in mice) and non-classical (Ly6C–) monocytes. However, additional functionally diverse monocyte subsets have recently been reported to be produced in the steady-state and under stress conditions such as infection. The molecular mechanisms underlying production of these subsets by bone marrow progenitors are poorly defined. Our studies have challenged the current, widely-accepted model of myelopoiesis and revealed 2 independent pathways of classical Ly6Chi monocyte production in the bone marrow: via granulocyte-monocyte progenitors (GMPs) and monocyte-DC progenitors (MDPs). We found that GMP- and MDP-derived Ly6Chi monocytes are morphologically distinct and exhibit differences in gene expression that are defined by their origins. GMP- derived Ly6Chi monocytes are larger and more granular than MDP-derived Ly6Chi monocytes, and enriched for granule proteins including myeloperoxidase. Thus GMP- and MDP-derived Ly6Chi monocytes appear to be functionally distinct. Moreover, we discovered that the two pathways of monocyte production are mobilized independently in response to microbial stimuli. For example, lipopolysaccharide (LPS) administration increases neutrophil and monocyte production by GMPs, while CpG DNA promotes monocyte and DC production by MDPs. Thus, the existence of two independent pathways of monocyte differentiation permits production of specific combinations of myeloid cell types during the emergency myelopoiesis response to pathogens. Our objective is to define pathways and mechanisms of monocyte production by GMPs and MDPs in the steady-state and in response to infection. In Aim 1, we will determine how myeloid transcription factors and epigenetic modifications shape the functional programming of Ly6Chi monocytes produced via the GMP and MDP pathways. In Aim 2, we will define the potential of GMP- and MDP-derived Ly6Chi monocytes to give rise to inflammatory macrophages and monocyte-derived DCs. In Aim 3, we will determine how LPS and CpG selectively target GMPs and MDPs to shape the repertoire of myeloid subsets produced. We have assembled a team of immunologists, hematologists and computational biologists to perform a set of experiments that will provide important insight into the molecular mechanisms that underlie the production of functionally diverse monocytes in the steady-state and under stress conditions. Moreover, our studies will lay the groundwork for the development of new translational approaches to specifically target functionally distinct monocyte subsets, which could be employed to promote immunity against pathogens or tumors, suppress inflammatory pathology, or facilitate tissue repair.

项目概要单核细胞是先天免疫细胞，在宿主防御感染和肿瘤方面具有多种功能作为组织稳态、修复和再生的单核细胞在整个组织中发挥监视作用。体内，并储存在骨髓中以快速募集到感染或受伤的组织中。在骨髓、血液和脾脏中发现功能不同的单核细胞：经典（小鼠中的 Ly6Chi）然而，还有其他功能多样的单核细胞亚群。最近有报道称，它是在稳态和感染等应激条件下产生的。骨髓祖细胞产生这些子集的分子机制尚不清楚。我们的研究挑战了当前广泛接受的骨髓生成模型，并揭示了 2 个独立的骨髓中经典 Ly6Chi 单核细胞产生的途径：通过粒细胞-单核细胞祖细胞 (GMP) 和单核细胞 DC 祖细胞 (MDP) 我们发现 GMP 和 MDP 衍生的 Ly6Chi 单核细胞是形态上不同，并表现出由其起源定义的基因表达差异。衍生的 Ly6Chi 单核细胞比 MDP 衍生的 Ly6Chi 单核细胞更大、颗粒更细，并且富含因此，GMP 和 MDP 衍生的 Ly6Chi 单核细胞似乎是颗粒蛋白。此外，我们发现单核细胞产生的两种途径是动员的。例如，脂多糖（LPS）的施用会增加。 GMPs 促进中性粒细胞和单核细胞的产生，而 CpG DNA 则通过以下方式促进单核细胞和 DC 的产生因此，单核细胞分化的两条独立途径的存在允许产生在对病原体的紧急骨髓生成反应过程中骨髓细胞类型的特定组合。我们的目标是定义 GMP 和 MDP 产生单核细胞的途径和机制在目标 1 中，我们将确定骨髓转录因子和感染的反应。表观遗传修饰塑造了通过 GMP 产生的 Ly6Chi 单核细胞的功能编程和在目标 2 中，我们将定义 GMP 和 MDP 衍生的 Ly6Chi 单核细胞产生的潜力。在目标 3 中，我们将确定 LPS 和 CpG 如何影响炎症巨噬细胞和单核细胞衍生的 DC。选择性地针对 GMP 和 MDP 来塑造所产生的骨髓亚群的库。我们组建了一个由免疫学家、血液学家和计算生物学家组成的团队来执行一系列实验将为了解产生这些物质的分子机制提供重要的见解此外，我们的研究将奠定稳态和应激条件下功能多样的单核细胞。开发新的转化方法以专门针对不同功能的基础单核细胞亚群可用于促进针对病原体或肿瘤的免疫力，抑制炎症病理学，或促进组织修复。