FUNCTIONAL DEVELOPMENT OF THE MAMMARY GLAND

本项目的目标是阐明乳腺两个关键发育转变的激素、分子和细胞机制：从怀孕到泌乳，以及从泌乳到复归时泌乳腺恢复到孕前状态。拟议的研究旨在为这些问题提供一种综合和合作的方法。在项目1中，将使用最先进的基因组和蛋白质组学技术检查妊娠和哺乳期过渡期间黄体酮停药和紧密连接关闭之间的关系。项目II将重点从孕激素受体、糖皮质激素受体与JAK/STAT信号转导通路的相互作用等方面阐述孕激素抑制妊娠期乳汁分泌的详细分子机制。在项目III中，将识别调节高尔基体物理扩张和泌乳过渡期间脂质分泌开始的分子，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在没有炎症的情况下从纠缠乳腺清除凋亡细胞的机制。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)用于改变功能途径的基因转导的腺病毒载体。实验将在体外和体内进行，使用先进的技术来检查在这些明确的上皮从一种生理状态到另一种生理状态的发育转变过程中基因表达和蛋白质组成的变化。这些研究将增强我们对乳腺发育和分泌调节的理解，并为许多器官中类似过程的调节提供一个很好的模型。由于母乳对婴儿营养至关重要，因此更好地了解这些转变将有助于改善婴儿营养，并有助于预防和治疗乳房疾病。

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.