Functional Development of the Mammary Gland

描述（由申请人提供）：美国儿科学会建议所有儿童至少在生命的前六个月母乳喂养，尽管有这样的建议，乳腺的功能发育和发育的结果，乳汁分泌，在过去的二十年中受到的关注相对较少。在这个项目中，我们寻求通过汇集六位具有不同专业知识的合格研究人员来检查乳汁分泌调节和机制的四个关键方面来弥补这一缺陷。在项目1中，我们将研究一个新的假设，即在乳腺中平衡糖酵解与脂质合成和细胞存活之间的联系。我们假设，丝氨酸/苏氨酸激酶Akt/PKB调控的己糖激酶活性/构象的变化是这两种功能之间的关键联系。我们将在转基因老鼠身上验证这一假设。在项目II中，我们将检查乳腺肺泡细胞中细胞质脂滴（CLD）形成的分子和细胞生物学基础，验证这些实体起源于内质网中包含所有必要合成机器的专门区域的假设。在项目III中，我们将仔细研究孕酮在妊娠后期抑制乳汁分泌的机制，包括直接和间接机制，以及它们在乳腺中对孕酮受体细胞和其他细胞的定位。将利用LacZ靶向孕酮受体编码区和绿色荧光蛋白靶向b-酪蛋白编码区的转基因小鼠菌株来实现这一目标。在项目四中，我们将开展PKC*在妊娠、哺乳和复归过程中对细胞增殖和凋亡的作用的研究。这种丝氨酸/苏氨酸激酶是上皮细胞凋亡的上游调节因子，我们将利用它来阐明乳瘀或激素停药损害乳腺上皮细胞存活的途径。这些研究将形成一个基础，在此基础上理解为什么哺乳并不总是进行得最好，从长远来看，应该有助于我们增加对婴儿的母乳供应，特别是早产儿，对他们来说，母乳是优先考虑的。

DESCRIPTION (provided by applicant): It is the recommendation of the American Academy of Pediatrics that all children be breast-fed for at least the first six months of life [2], Despite this recommendation, the functional development of the mammary gland and the result of that development, milk secretion, have received relatively little attention over the past two decades. In this program project we seek to remedy this deficit by bringing together six well-qualified investigators with varying expertise to examine four critical aspects of the regulation and mechanism of milk secretion. In Project I we will examine a new hypothesis that links balanced glycolysis in the mammary gland both to lipid synthesis and cell survival. We hypothesize that changes in the activity/ conformation of hexokinase regulated by the serine/threonine kinase Akt/PKB provide the crucial link between these two functions. We will test the hypothesis in genetically altered mice. In Project II, we will examine the molecular and cell biological basis of the formation of cytoplasmic lipid droplets (CLD) in the mammary alveolar cell, testing the hypothesis that these entities originate within specialized domains in the endoplasmic reticulum containing all the necessary synthetic machinery machine for their synthesis. In project III, we will scrutinize the mechanisms by which progesterone inhibits the initiation of milk secretion in late pregnancy examining both direct and indirect mechanisms and their localization in the mammary gland to progesterone receptor containing cells and other cells. Strains of genetically altered mice in which the LacZ has been targeted to the progesterone receptor coding region and green fluorescent protein to the b-casein coding region will be used to accomplish this aim. In Project IV we will initiate studies of the role of PKC* on cell proliferation and apoptosis in pregnancy, lactation and involution. This serine/threonine kinase is an upstream regulatory factor in epithelial cell apoptosis and we will use it to elucidate the pathways through which mammary epithelial cell survival can be compromised by milk stasis or hormone withdrawal. These studies will form a foundation on which to base an understanding of why lactation does not always proceed optimally and in the long run should help us increase the human milk supply for infants, particularly preterm infants, for whom human breast milk is a priority.