FUNCTIONAL DEVELOPMENT OF THE MAMMARY GLAND

乳腺的功能发育

• 批准号: 6388172
• 负责人: MARGARET Cobb NEVILLE
• 金额: $ 90.96万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-23 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6388172
• 关键词: lactation; mammary gland; pregnancy; reproductive development

The goal of this Program Project is to elucidate the hormonal, molecular, and cellular mechanisms involved in two critical developmental transitions in the mammary gland: those from pregnancy to lactation, and from lactation to the return of the lactating gland to its pre-pregnant state at involution. The proposed research is designed to provide an integrated and cooperative approach to these problems. In Project I, the relationship between progesterone withdrawal and tight junction closure during the transition between pregnancy and lactation will be examined using state of the art genomic and proteomic technology. In Project II the detailed molecular mechanisms by which progesterone inhibits milk secretion during pregnancy will be elucidated focusing on interactions between the progesterone receptor, the glucocorticoid receptor and the JAK/STAT signal transduction pathway. In Project III the molecules that regulate the physical expansion of the Golgi and the onset of mil lipid secretion during the transition to lactation will be identified and their functional significance assessed. Finally, in Project IV the mechanisms by which mammary epithelial cells and macrophages remove apoptotic cells from the involuting mammary gland in the absence of inflammation will be studied. Three cores will provide (A) administrative support, (B) specialized animal breeding and surgical support and (C) adenovirus vectors for use in transduction of genes designed to alter functional pathways. Experiments will be carried out in vitro and in vivo using advanced techniques to examine changes in gene expression and protein composition during these well-define developmental transitions of the epithelium from one physiological state to another. These studies should enhance our understanding of developmental and secretory regulation in the mammary gland and provide an excellent model for the regulation of similar processes in many organs. Because milk is critically important to infant nutrition, better insight into these transitions should lead to improve infant nutrition as well as contribute to the prevention and cure of breast diseases.

该计划项目的目的是阐明乳腺中两个关键发育转变的激素，分子和细胞机制：从妊娠到泌乳的荷尔德，从泌乳到哺乳期，再到泌乳腺到返回其前孕妇的先知状态。拟议的研究旨在为这些问题提供综合和合作的方法。在项目I中，将使用最先进的基因组和蛋白质组学技术的状态检查怀孕和泌乳之间的孕酮戒断与紧密连接闭合之间的关系。在项目II中，将阐明孕酮在怀孕期间抑制牛奶分泌的详细分子机制，将重点关注孕酮受体，糖皮质激素受体和JAK/STAT信号转导途径之间的相互作用。在项目III中，将确定调节高尔基体物理膨胀的分子以及在过渡到泌乳过程中MIL脂质分泌的发作，并评估其功能意义。最后，在项目IV中，将研究乳腺上皮细胞和巨噬细胞从肿瘤腺体中去除凋亡细胞的机制。三个核心将提供（a）行政支持，（b）专门的动物育种和手术支持，以及（c）用于转导旨在改变功能途径的基因的腺病毒载体。实验将在体外和体内使用高级技术进行，以检查上皮细胞从一种生理状态到另一种定义的良好定义的发育过渡期间的基因表达和蛋白质组成的变化。这些研究应增强我们对乳腺中发育和分泌调节的理解，并为许多器官的相似过程提供了一个极好的模型。由于牛奶对婴儿的营养至关重要，因此更好地了解这些过渡应该会改善婴儿营养，并有助于预防和治愈乳腺癌。