Functions of ductal- and stromal-associated macrophages in the mammary gland

乳腺导管和基质相关巨噬细胞的功能

• 批准号: 10700123
• 负责人: Heather L Machado
• 金额: $ 48.44万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-07 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700123
• 关键词: Ablation; Adult; Alveolar; Anti-Inflammatory Agents; Automobile Driving; Bioinformatics; Breast Cancer Risk Factor; CSF1R gene; Cell Differentiation process; Cells; Collagen; Data; Deposition; Development; Diestrus; Disease; Duct (organ) structure; Ductal Epithelium; Epithelium; Equilibrium; Estrous Cycle; Event; Extracellular Matrix; Follow-Up Studies; Gene Expression Profile; Genetic; Genomic approach; Genomics; Goals; Health; Heterogeneity; Homeostasis; Hot Spot; Impairment; Laboratories; Lactation; Macrophage; Mammary Gland Parenchyma; Mammary gland; Mediating; Mus; Myeloid Cells; Neoplasm Metastasis; Nulliparity; Organ; Phenotype; Population; Population Analysis; Predisposition; Pregnancy; Publishing; Regulation; Role; Structure; Tissues; Transplantation; conditional knockout; cytokine; genetic approach; insight; mammary; mammary gland development; postnatal development; response; stem cell expansion; tissue repair; transcription factor; tumor progression; tumorigenesis; uptake

PROJECT SUMMARY Tissue resident macrophage function has emerged as a critical component controlling the balance between organ health and disease. In the mammary gland, macrophages are closely associated with the ductal epithelium and have important phagocytotic roles to maintain tissue homeostasis. Recent studies from our laboratory and others revealed distinct ductal- and stromal-associated tissue resident macrophages that contribute to maintaining the developing ductal structures. However, the important macrophage-derived factors that regulate mammary gland development and the mechanisms by which these distinct macrophage populations maintain the homeostatic state are poorly understood. The overall goal of these studies is to define the functions and mechanisms by which tissue resident macrophages contribute to ductal remodeling throughout distinct stages of mammary gland development. Our preliminary studies identify transcriptional profiles of distinct macrophage populations in the mammary glands of adult mice. We show that two key factors, Cebpb and Gas6, are highly expressed in ductal- and stromal-associated macrophages, respectively, providing potential mechanisms for macrophage function in mammary gland development. Genetic ablation of these factors results in alterations in the mammary gland during key developmental windows. We hypothesize that C/EBPb and Gas6 are crucial effector molecules that drive distinct functions of ductal and stromal macrophages, respectively, during key stages of mammary gland development. In aim 1, we will characterize macrophage heterogeneity throughout postnatal development and determine the functions of distinct macrophage populations in mammary gland development. In Aim 2, the mechanisms of how C/EBPb-induced factors in ductal macrophages alter stem cell expansion will be determined. In Aim 3, Gas6-dependent mechanisms of collagen homeostasis by stromal macrophages will be determined. Impact: Throughout mammary gland development, there are critical windows that are highly susceptible to mutagenic events. Although macrophages have been well-studied during tumor progression and metastasis, the mechanisms driving tissue resident macrophage function during these key stages of development are not known. Understanding these mechanisms will advance our understanding of how tissue resident macrophages impact mammary tissue homeostasis, and provide insight into how disrupted tissue homeostasis leads to disease, such as tumorigenesis.

项目摘要 组织驻留巨噬细胞功能已成为控制平衡的关键组成部分 器官健康和疾病之间的联系在乳腺中，巨噬细胞与 导管上皮，并具有重要的吞噬作用，以维持组织的稳态。最近的研究来自 我们的实验室和其他实验室揭示了不同的导管和间质相关的组织驻留巨噬细胞， 有助于维持发育中的导管结构。然而，重要的巨噬细胞衍生因子 调节乳腺发育的机制以及这些不同的巨噬细胞 种群维持内稳态的机制知之甚少。这些研究的总体目标是确定 组织内巨噬细胞参与导管重塑的功能和机制 在乳腺发育的不同阶段。我们的初步研究确定了转录 成年小鼠乳腺中不同巨噬细胞群体的分布图。我们发现，两个关键 因子Cebpb和Gas 6分别在导管和基质相关巨噬细胞中高度表达， 为乳腺发育中巨噬细胞功能提供了潜在机制。的基因切除 这些因素导致乳腺在关键发育期发生变化。我们假设 C/EBPb和Gas6是驱动导管和间质不同功能的关键效应分子， 巨噬细胞，分别在乳腺发育的关键阶段。在目标1中，我们将描述 巨噬细胞异质性在整个出生后的发展，并确定不同的功能， 巨噬细胞群在乳腺发育中的作用。目的2：探讨C/EBPb诱导细胞凋亡的机制。 将确定导管巨噬细胞中改变干细胞扩增的因素。在目标3中，Gas6依赖性 将确定基质巨噬细胞的胶原体内平衡机制。影响：整个 乳腺发育，存在对致突变事件高度敏感的关键窗口。 尽管巨噬细胞在肿瘤进展和转移过程中的作用已得到充分研究， 在这些发育的关键阶段期间驱动组织驻留巨噬细胞功能是未知的。 了解这些机制将促进我们对组织驻留巨噬细胞如何影响 乳腺组织稳态，并提供了对组织稳态破坏如何导致疾病的见解， 例如肿瘤发生。