Functional Development of the Mammary Gland

描述（由申请人提供）：哺乳对所有哺乳动物的生存至关重要，因为它支持新生儿的生长。成功的泌乳需要完成泌乳前的所有发育阶段，包括主要由雌激素刺激的青春期发育，孕早期由孕酮和催乳素驱动的分泌腺泡扩张，妊娠晚期发生的分泌分化，以及分娩时发生的分泌激活。任何阶段的失败往往会导致无效的泌乳，表现为新生儿生长不足或死亡。尽管在乳腺生物学方面取得了实质性的进展，但我们对哺乳的理解仍存在很大的差距。虽然在乳蛋白基因调控方面取得了很大进展，但我们对脂质生物合成的理解却落后于人。在过去的十年中，我们的小组在科罗拉多大学医学院，一直专注于分泌分化和激活，越来越多的关注脂质代谢和合成的脂质成分的牛奶。该项目资助的首要假设是，乳腺发育不是由单一的主控制基因控制的，而是一个精心设计的“遗传调节因子”，控制妊娠中期，妊娠后期和分泌激活期间的发育。在项目I中，我们将研究Aktl在调节分泌激活时发生的“脂质开关”中的作用-参与脂质生物合成的酶的协调转录激活。在项目II中，我们将研究孕激素和胰岛素在妊娠期肺泡发育中的作用。在项目III中，我们将研究microRNA在乳腺发育中的作用，特别关注它们调节代谢变化和类固醇激素受体信号传导的能力。在项目IV中，我们将重点关注细胞质脂滴的形成是如何调节的。这些项目得到两个核心的协助：一个是行政核心，负责监督财政问题并提供后勤支助;另一个是腺病毒核心，负责制备供项目使用的重组人腺病毒载体。这一协调一致的努力将为理解与糖尿病和/或肥胖相关的女性泌乳失败提供机制基础。

DESCRIPTION (provided by applicant): Lactation is critical to survival of all mammals because it supports the growth of the newborn. Successful lactation requires completion of all developmental stages proceeding lactation, including pubertal development largely stimulated by estrogen, expansion of the secretory alveoli in early pregnancy driven by progesterone and prolactin, secretory differentiation occurring during late pregnancy, and secretory activation that occurs at parturition. A failure at any stage often results in ineffective lactation, indicated by either inadequate growth or death of newborns. Despite substantive advances in mammary gland biology, substantial gaps in our understanding of lactation exist. While great advances have been made regarding regulation of milk protein genes, our understanding of lipid biosynthesis has lagged behind. During the last ten years our group at the University of Colorado School of Medicine, has focused on secretory differentiation and activation with an increasing focus upon lipid metabolism and synthesis of lipid component of milk. The overarching hypothesis of this program project grant is that mammary gland development is not controlled by a single master controller gene, but rather a carefully patterned progression of "genetic regulators" that control development during mid-pregnancy, late pregnancy, and secretory activation. In Project I we will examine the role of Aktl in regulating the "lipid switch" that occurs at secretory activation- the coordinate transcriptional activation of enzymes involved in lipid biosynthesis. In Project II we will examine the role of progesterone and insulin in alveolar development during pregnancy. In Project III we will examine the role of microRNAs in mammary gland development with particular focus on their ability to modulate metabolic changes and signaling by steroid hormone receptors. In Project IV we will focus on how formation of cytoplasmic lipids droplets is regulated. These projects are assisted by two Cores: an Administrative Core that oversees fiscal issues and provides logistic support and the Adenovirus Core that prepares recombinant human adenoviral vectors for use in the projects. This concerted effort will provide mechanistic underpinnings for understanding lactation failure in women related to diabetes and/or obesity.