Functional Development of the Mammary Gland

描述(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成长。成功的哺乳需要完成哺乳期的所有发育阶段，包括主要由雌激素刺激的青春期发育，孕酮和催乳素驱动的早孕分泌肺泡的扩张，妊娠晚期的分泌分化，以及分娩时的分泌激活。任何阶段的失败往往会导致哺乳效率低下，表现为新生儿发育不充分或死亡。尽管乳腺生物学取得了实质性进展，但我们对哺乳的理解仍然存在很大差距。虽然在乳蛋白基因的调控方面已经取得了很大的进展，但我们对脂肪生物合成的理解却相对滞后。在过去的十年里，我们科罗拉多大学医学院的团队一直专注于分泌分化和激活，并越来越关注牛奶的脂肪代谢和脂肪成分的合成。这项计划项目拨款的主要假设是，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控制怀孕中期、怀孕后期和分泌激活期间发育的“基因调节器”的发展过程。在项目I中，我们将研究Aktl在调节“脂开关”中的作用，这种“脂开关”发生在分泌激活--参与脂生物合成的酶的协调转录激活中。在项目II中，我们将研究孕酮和胰岛素在孕期肺泡发育中的作用。在项目III中，我们将研究microRNAs在乳腺发育中的作用，特别关注它们通过类固醇激素受体调节代谢变化和信号传递的能力。在项目IV中，我们将重点介绍细胞质脂滴的形成是如何受到调控的。这些项目得到两个核心的协助：一个负责监督财政问题并提供后勤支持的行政核心，以及一个准备用于这些项目的重组人腺病毒载体的腺病毒核心。这种协调一致的努力将为理解与糖尿病和/或肥胖有关的女性哺乳失败提供机械基础。

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.