Functional Development of the Mammary Gland

乳腺的功能发育

• 批准号: 7104968
• 负责人: MARGARET Cobb NEVILLE
• 金额: $ 105.98万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-23 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104968
• 关键词: genetically modified animals; laboratory mouse; lactation; mammary gland; pregnancy; reproductive development

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.

描述（由申请人提供）：美国儿科学院的建议至少在生命的前六个月中，所有儿童都被喂养了[2]，尽管有建议，但乳腺的功能发展以及在过去的二十年中，牛奶分泌的结果，牛奶分泌的结果很少。在这个计划项目中，我们试图通过将六位具有不同专业知识的合格调查人员汇集在一起​​来纠正这种赤字，以研究牛奶分泌的调节和机制的四个关键方面。在项目I中，我们将研究一个新的假设，该假设将乳腺中平衡的糖酵解与脂质合成和细胞存活联系起来。我们假设由丝氨酸/苏氨酸激酶Akt/pKB调节的己糖激酶的活性/构象的变化提供了这两个功能之间的关键联系。我们将检验遗传改变的小鼠的假设。在项目II中，我们将研究乳腺细胞中细胞质脂质液滴（CLD）的形成的分子和细胞生物学基础，检验了这些实体在内质网中源自内质网中包含所有必要的合成机器中其合成的假设。在项目III中，我们将仔细检查孕激素在妊娠晚期中抑制牛奶分泌的机制，以检查直接和间接机制，及其在乳腺中的定位对含有孕激素受体的细胞和其他细胞的定位。遗传改变的小鼠的菌株将使用LACZ靶向孕酮受体编码区域，而绿色荧光蛋白将用于B-casein编码区域，以实现这一目标。在IV项目中，我们将启动研究PKC*在妊娠，泌乳和涉及妊娠中的细胞增殖和凋亡中的作用。这种丝氨酸/苏氨酸激酶是上皮细胞凋亡中的上游调节因子，我们将使用它来阐明乳腺上皮细胞存活可能会因牛奶暂停或激素戒断而损害的途径。这些研究将构成一个基础，以理解为什么泌乳并不总是最佳地进行，从长远来看，应该有助于我们增加人类乳的供应，尤其是早产儿的人类乳的供应。