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.

项目总结 组织驻留巨噬细胞功能已成为控制平衡的关键组件 器官健康和疾病之间的关系。在乳腺中，巨噬细胞与 导管上皮细胞具有重要的吞噬作用，以维持组织内环境的稳定。最近来自 我们的实验室和其他实验室发现了明显的导管和间质相关组织驻留的巨噬细胞 有助于维护正在发展的管道结构。然而，重要的巨噬细胞衍生因子 调节乳腺发育以及这些不同的巨噬细胞 维持动态平衡状态的种群对此知之甚少。这些研究的总体目标是确定 组织驻留巨噬细胞在导管重塑中的作用和机制 贯穿于乳腺发育的不同阶段。我们的初步研究确定了转录 成年小鼠乳腺内不同巨噬细胞群的分布。我们展示了两个关键字 CEBPB和Gas6因子分别在导管相关巨噬细胞和基质相关巨噬细胞中高表达， 为巨噬细胞在乳腺发育中的作用提供了潜在的机制。遗传性消融 这些因素会导致乳腺在关键发育窗口期发生变化。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 巨噬细胞在出生后发育过程中的异质性和决定其功能的不同 乳腺发育中的巨噬细胞群。在目标2中，C/EBPb诱导的机制 干细胞扩增后导管巨噬细胞中的因素将被确定。在Aim 3中，依赖于Gas6 基质巨噬细胞的胶原动态平衡机制将被确定。影响：贯穿始终 在乳腺发育过程中，有一些关键的窗口非常容易受到突变事件的影响。 虽然巨噬细胞在肿瘤进展和转移过程中已经得到了很好的研究，但其机制 在这些关键的发育阶段，驱动组织驻留巨噬细胞的功能尚不清楚。 了解这些机制将促进我们对组织驻留巨噬细胞如何影响 乳腺组织动态平衡，并提供关于组织动态平衡被破坏如何导致疾病的洞察， 比如肿瘤的发生。