Functional Development of the Mammary Gland

乳腺的功能发育

基本信息

批准号：
8062791
负责人：
STEVEN M ANDERSON
金额：
$ 23.64万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8062791
关键词：
Academy Adenovirus Vector Adenoviruses Administrator Adrenalectomy Alveolar Cell Alveolus American Animals Antibodies Apoptosis Apoptotic Architecture Attention Biochemical Biochemistry Biological Biology Biophysics Birth Breast Feeding Budgets CD36 gene Caseins Cell Proliferation Cell Survival Cells Characteristics Child Chromatin Structure Code Collaborations Complement Complex Data Development Developmental Process Direct Costs Discipline of obstetrics Doctor of Philosophy Drops Endocytosis Endoplasmic Reticulum Endotoxins Epithelial Cells Epithelium Equilibrium Event Exocytosis FVB Mouse Fatty acid glycerol esters Foundations Funding Gene Expression Genes Gland Glycolysis Goals Golgi Apparatus Grant Green Fluorescent Proteins Grouping Gynecology Hormonal Hormones Hour Human Human Milk Immune system Immunoglobulin A Individual Infant Inflammation Inflammatory Injection of therapeutic agent Integrins Investigation Laboratories Laboratory Personnel LacZ Genes Lactation Left Life Link Lipid Inclusion Lipids Liver Mammals Mammary gland Mediating Medical Research Medical center Medicine Metabolism Methods Microarray Analysis Microscopic Milk Milk Proteins Molecular Molecular Biology Molecular Conformation Mus Ovariectomy Paper Pathology Pathway interactions Pediatrics Phase Phosphorylation Physiology Play Positioning Attribute Postdoctoral Fellow Pregnancy Premature Infant Preparation Principal Investigator Process Production Progesterone Progesterone Receptors Progress Reports Protein Biosynthesis Protein-Serine-Threonine Kinases Proteins Proteome Proteomics Publications Publishing Qualifying Recommendation Regulation Reporting Repression Research Research Personnel Residual state Role Running Scientist Series Services Surface System TGFB1 gene Techniques Technology Testing Tight Junctions Time Transplantation Virus Vitronectin Receptors Weaning Withdrawal Work Writing Xanthine Oxidase adipophilin base claudin 3 college cytokine design follower of religion Jewish graduate student hexokinase in vivo inhibitor/antagonist instructor interest interstitial macrophage mammary epithelium mammary gland development mastitis meetings member milk fat globule occludin operation phosphatidylserine receptor pregnant prevent professor programs promoter receptor response structural biology tool

项目摘要

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. T his 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.

美国儿科学会建议所有儿童至少在生命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发育的结果，乳汁分泌，在过去二十年里受到的关注相对较少。在这个项目中，我们试图通过聚集六名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。在项目一中，我们将研究一个新的假设，该假设将乳腺中的平衡糖酵解与脂质合成和细胞存活联系起来。我们假设丝氨酸/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。我们将在基因改造小鼠中检验这一假设。在项目 II 中，我们将研究乳腺泡细胞中细胞质脂滴 (CLD) 形成的分子和细胞生物学基础，检验这些实体起源于包含所有必要的合成机器的内质网专门域的假设用于它们的合成。在项目 III 中，我们将仔细研究黄体酮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对含有黄体酮受体的细胞和其他细胞的定位。将使用基因改造小鼠品系来实现这一目标，其中 LacZ 已靶向黄体酮受体编码区，绿色荧光蛋白已靶向 b-酪蛋白编码区。在项目 IV 中，我们将启动 PKC* 对妊娠期、哺乳期和复旧期细胞增殖和凋亡的作用的研究。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因乳汁停滞或激素撤退而受到损害的途径。这些研究将为理解为什么哺乳并不总是以最佳状态进行进行奠定基础，从长远来看，应该有助于我们增加婴儿的母乳供应，特别是早产儿，对他们来说母乳是优先考虑的。