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

虽然孕激素和催乳素在乳腺发育中的作用已被广泛研究， 研究表明，胰岛素，IGF 1和IGF 2的作用受到的关注要少得多。内维尔实验室 最近发现，胰岛素受体（IR）的无效突变，特别是在分泌上皮细胞， 在妊娠早期阻碍增殖活性，在妊娠晚期在很大程度上抑制分泌分化。 怀孕我们假设这种受体和它的一种或多种配体是重要的调节剂， 乳腺分化类似地，在乳腺癌中对孕酮受体（PR）的广泛研究， 腺显示孕酮和PR是肺泡增殖和发育所必需的。那里 这也证明了IR和PR共同调节彼此的活动，尽管几乎没有什么是 了解机制。在这个项目中，内维尔博士和公共关系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，来研究这个新领域。体外 实验将利用来自处女和15天的乳腺上皮细胞的独特3D腺泡培养物 妊娠小鼠，以阐明这两种调节途径的分子机制， 乳腺的增殖和分化。研究人员还将使用小鼠模型， 低胰岛素血症和高胰岛素血症，以检查饥饿、糖尿病和肥胖等疾病 影响这些通路，并通过它们影响乳汁分泌。肥胖，一种越来越常见的疾病 在大多数发展中国家，母乳喂养通常与母乳喂养失败有关。 对婴儿最有好处。了解肥胖改变乳腺癌的机制 发育和哺乳能力可能提供新的治疗方式， 母乳喂养的成功 相关性（参见说明）： 肥胖症是一个全球性的主要健康问题，对母乳喂养产生负面影响。通常 怀孕期间血浆胰岛素水平升高;我们机构的初步数据显示， 肥胖妇女的情况。我们的研究提供了一个可能的机制之间的联系，胰岛素对乳腺癌的影响， 发育，哺乳失败和乳腺癌的发展为我们提供了诊断的基础， 和潜在的治疗干预

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