Regulation of tissue resident macrophages during mammary gland development

项目摘要 乳腺发育需要乳腺上皮细胞和乳腺癌细胞之间复杂的相互作用。 他们周围的环境。组织驻留巨噬细胞存在于乳腺中， 与发育中的上皮结构和脂肪基质相关，并且已知是重要的 有助于乳腺发育和维持组织稳态。了解这些 机制对于确定巨噬细胞功能改变对巨噬细胞功能丧失的后果至关重要。 稳态和促进组织特异性疾病，如肿瘤发生。该项目的目标是 描绘了维持组织驻留巨噬细胞在乳腺中的稳态的机制， 并确定这些机制的改变是否会影响乳腺发育。在 初步研究，我们已经开发出一种新的方法，用于识别和分离不同的人群， 来自乳腺的常驻巨噬细胞，包括与上皮结构相关的巨噬细胞 以及与基质区相关的那些。在初步研究的基础上，我们提出， 和转录激活因子（STAT）途径是乳腺巨噬细胞的关键调节因子， 腺和这些途径的失调导致巨噬细胞的形成， 允许肿瘤发生的环境。拟议的研究将1）确定 乳腺发育期间组织驻留巨噬细胞群体，2）证明了 STAT作为乳腺中组织驻留巨噬细胞的关键转录调节因子，以及3） 确定炎症因子对乳腺内巨噬细胞功能的影响。最近 研究集中在理解驱动组织驻留巨噬细胞功能的机制及其在细胞内的表达。 对组织发育和体内平衡的贡献。然而，关于这一点，人们所知甚少。 驱动乳腺中常驻巨噬细胞功能的机制。了解这些机制 将提供深入了解如何改变居民巨噬细胞的功能，如通过局部或全身 炎症信号，影响上皮形态发生并导致癌症风险。

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.