Regulation of tissue resident macrophages during mammary gland development

乳腺发育过程中组织驻留巨噬细胞的调节

• 批准号: 9769803
• 负责人: Kathryn L Schwertfeger
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769803
• 关键词: Adipose tissue; Automobile Driving; Breast Epithelial Cells; Coculture Techniques; Complex; Development; Dimensions; Disease; Duct (organ) structure; Ductal; Embryo; Environment; Epithelial; Erinaceidae; Exhibits; Gene Expression Profiling; Genetic; Genetic Transcription; Goals; Health; Hematopoietic; Homeostasis; Human; Hyperplasia; Inflammation; Inflammatory; Interleukin-6; Lactation; Lesion; Mammary gland; Methods; Modeling; Morphogenesis; Mus; Myelogenous; Myeloid Cells; Pathway interactions; Phenotype; Population; Production; Puberty; Regulation; Research; STAT protein; STAT3 gene; Signal Transduction; Source; Structure; Tissues; base; cancer risk; cytokine; genetic approach; insight; macrophage; mammary gland development; mouse model; novel; smoothened signaling pathway; source localization; tumorigenesis

PROJECT SUMMARY Mammary gland development requires complex interactions between mammary epithelial cells and their surrounding environment. Tissue resident macrophages are present in the mammary gland in close association with developing epithelial structures and within the adipose stroma, and are known to be important for contributing to mammary gland development and maintaining tissue homeostasis. Understanding these mechanisms is critical for determining the consequences of altered macrophage function on loss of homeostasis and promotion of tissue specific disease, such as tumorigenesis. The goal of this project is to delineate the mechanisms that maintain tissue resident macrophages in the mammary gland in a homeostatic state and to determine whether the altering these mechanisms impacts mammary gland development. In preliminary studies, we have developed a novel method for identifying and isolating distinct populations of resident macrophages from the mammary gland, including macrophages associated with epithelial structures and those associated with stromal regions. Based on preliminary studies, we propose that signal transducer and activator of transcription (STAT) pathways are key regulators of resident macrophages in the mammary gland and that deregulation of these pathways results in the formation of macrophages that create a permissive environment for tumorigenesis. Proposed studies will 1) determine the source and localization of tissue resident macrophage populations during mammary gland development, 2) demonstrate the importance of STATs as key transcriptional regulators of tissue resident macrophages in the mammary gland and 3) determine the effects of inflammatory factors on resident macrophage function in the mammary gland. Recent studies have focused on understanding the mechanisms driving tissue resident macrophage function and their contributions to tissue development and homeostasis. However, relatively little is known regarding the mechanisms driving resident macrophage function in the mammary gland. Understanding these mechanisms will provide insights into how alterations in resident macrophage function, such as by local or systemic inflammatory signals, impact epithelial morphogenesis and contribute to cancer risk.

项目摘要 乳腺发育需要乳腺上皮细胞与 他们周围的环境。乳腺中存在组织驻留巨噬细胞 与发展上皮结构和脂肪基质内的关联，已知很重要 有助于乳腺发育并维持组织稳态。了解这些 机制对于确定改变巨噬细胞功能对损失的后果至关重要 稳态和组织特异性疾病的促进，例如肿瘤发生。这个项目的目标是 描述维持乳腺内组织驻留组织巨噬细胞的机制 状态并确定改变这些机制是否会影响乳腺发育。在 初步研究，我们开发了一种新的方法来识别和隔离不同的种群 来自乳腺的居民巨噬细胞，包括与上皮结构相关的巨噬细胞 以及与基质区域相关的。根据初步研究，我们提出了信号传感器 转录（Stat）途径的激活因子是乳腺中常驻巨噬细胞的关键调节剂 腺体和对这些途径的放松管制导致巨噬细胞的形成 肿瘤发生的允许环境。拟议的研究将确定确定的来源和定位 乳腺发育过程中组织驻留巨噬细胞种群，2）证明了重要性 统计数据是乳腺中组织驻留巨噬细胞的关键转录调节剂，3） 确定炎症因子对乳腺中常驻巨噬细胞功能的影响。最近的 研究的重点是理解驱动组织驻留巨噬细胞功能及其的机制 对组织发育和稳态的贡献。但是，关于 驱动乳腺中驻留巨噬细胞功能的机制。了解这些机制 将提供有关居民巨噬细胞功能的变化的见解，例如本地或系统 炎症信号，影响上皮形态发生并导致癌症风险。