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出生后的前六个月进行母乳喂养[2]，尽管有此建议，但乳腺的功能发育及其结果，即乳汁分泌，在过去二十年中受到的关注相对较少。在这个项目中，我们试图通过汇集六名具有不同专业知识的合格研究人员来研究乳汁分泌的调节和机制的四个关键方面来弥补这一缺陷。在项目I中，我们将研究一个新的假设，即乳腺糖酵解平衡与脂质合成和细胞存活之间的联系。我们推测丝氨酸/苏氨酸激酶Akt/PKB调节的己糖激酶活性/构象的变化提供了这两种功能之间的关键联系。我们将在转基因小鼠中检验这一假设。在项目II中，我们将研究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，测试这些实体起源于内质网中包含所有必要的合成机器机器的专门领域的假设。在项目III中，我们将详细研究孕激素抑制妊娠晚期乳汁分泌的机制，检查直接和间接机制及其在乳腺中的孕激素受体细胞和其他细胞的定位。将使用基因改变的小鼠品系来实现这一目的，其中LacZ已经靶向孕酮受体编码区，绿色荧光蛋白靶向b-酪蛋白编码区。在项目IV中，我们将开始研究PKC* 在妊娠、哺乳和退化中对细胞增殖和凋亡的作用。这种丝氨酸/苏氨酸激酶是上皮细胞凋亡的上游调节因子，我们将用它来阐明乳腺上皮细胞存活的途径，通过这种途径可以受到乳汁淤积或激素戒断的影响。这些研究将为理解为什么哺乳并不总是以最佳方式进行奠定基础，从长远来看，这些研究将有助于我们增加婴儿的母乳供应，特别是早产儿，母乳是他们的优先事项。

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.