Mammary Alveoiar Development in the Pregnant Mouse: Role of the Insulin & Proges

尽管孕酮和催乳素在乳腺发育中的作用已被广泛研究 在研究中，胰岛素、IGF1和1GF2的作用受到的关注要少得多。奈维尔实验室 最近发现，胰岛素受体(IR)的零突变专门存在于分泌上皮细胞中 在妊娠早期阻碍增殖活动，在晚期在很大程度上抑制分泌分化 怀孕了。我们假设该受体及其一个或多个配体是重要的调节因子。 乳腺分化。同样，对乳腺中的孕激素受体(PR)进行了广泛的研究 腺体显示黄体酮和孕激素是肺泡增殖和发育所必需的。那里 这也是IR和PR共同工作来调节彼此的活动的证据，尽管几乎没有什么是 知道其中的机制。在这个项目中，内维尔博士和公关专家爱德华兹博士将与 两位新陈代谢专家，Carrie McCurdy博士和Paul MacLean博士，研究这一新领域。离体 实验将利用原始和15日龄乳腺上皮细胞的独特3D腺泡培养 以阐明这两条调控通路引导两条途径的分子机制 乳腺的增殖和分化。调查人员还将使用小鼠模型 低胰岛素血症和高胰岛素血症检查饥饿、糖尿病和肥胖等情况 冲击这些途径，并通过它们影响乳汁分泌。肥胖，一种日益常见的疾病 在大多数发展中国家，在母乳喂养不足的人群中，往往与哺乳失败有关 对婴儿来说可能是最有益的。了解肥胖改变乳房的机制 发育和哺乳能力可能提供新的治疗方式，将增强 母乳喂养的成功。 相关性(请参阅说明)： 肥胖是全球范围内的一个主要健康问题，对母乳喂养性能产生负面影响。正常 妊娠期血浆胰岛素水平上升；我们机构的初步数据显示，上升幅度更高 在肥胖女性身上。我们的研究提供了胰岛素对乳腺的影响之间可能的机制联系 发育、哺乳失败和乳腺癌的发展为我们提供了这两种诊断的基础 和非标志性的治疗干预

Although the roles of progesterone and prolactin in mammary gland development have been extensively studied, the roles of Insulin, IGF1 and 1GF2 have received much less attention. The Neville laboratory recently found that a null mutation of the insulin receptor (IR) specifically in the secretory epithelium both impedes proliferative activity in eariy pregnancy and largely inhibits secretory differentiation in late pregnancy. We hypothesize that this receptor and one or more of its ligands are important modulators of mammary differentiation. Similariy, extensive work with the progesterone receptor (PR) in the mammary gland has shown that progesterone and PR are necessary for alveolar proliferation and development. There is also evidence that IR and PR work together to modulate each other's activity, although almost nothing is known about the mechanisms. In this project Dr. Neville and Dr. Edwards, an expert on PR, will work with two experts in metabolism, Drs. Carrie McCurdy and Paul MacLean, to investigate this new area. In vitro experiments will utilize unique 3D acinar cultures of mammary epithelial cells from virgin and 15 day pregnant mice to elucidate the molecular mechanisms by which these two regulatory pathways direct both proliferation and differentiation in the mammary gland. The investigators will also use mouse models of hypoinsulinemia and hyperinsulinemia to examine how conditions such as starvation, diabetes and obesity impinge on these pathways, and through them on milk secretion. Obesity, an increasingly common condition in most developing countries, is often associated with lactation failure in a population where breastfeeding is likely to be most beneficial to the infant. Understanding the mechanisms by which obesity alters mammary development and lactation competence may provide new therapeutic modalities that will enhance breastfeeding success. RELEVANCE (See instructions): Obesity is a primary health concern woridwide that negatively impacts breastfeeding performance. Normally plasma insulin levels rise during pregnancy; preliminary data from our institution show that the rise is higher in obese women. Our studies offer a possible mechanistic link between the effects of insulin upon mammary development, lactation failure, and breast cancer development providing us with the basis for both diagnostic and notential therapeutic interventions