Regulation of Secretory Activation by Akt1 the Fatty Acid Switch

Akt1（脂肪酸开关）对分泌激活的调节

• 批准号: 8379420
• 负责人: Steven M Anderson
• 金额: $ 19.3万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8379420
• 关键词: Address; Affect; Alveolus; Biological; Birth; Brain; Caliber; Cell Line; Cell Survival; Cells; Defect; Development; Diabetes Mellitus; Dietary intake; Disease; Doctor of Philosophy; Energy Metabolism; Epithelial Cells; Equilibrium; Estrogen Receptors; Event; Fatty Acids; Fatty acid glycerol esters; Foundations; Functional disorder; Gene Expression; Gene Proteins; Genes; Genetic; Growth; Health; In Vitro; Instruction; Insulin; JAK2 gene; Knockout Mice; Laboratories; Lactation; Lactose; Lipids; Mammary gland; Metabolic; Metabolic Activation; Metabolism; Milk; Milk Proteins; Modeling; Molecular; Molecular Analysis; Mouse Mammary Tumor Virus; Mus; Newborn Infant; Nurses; Nutrient; Obesity; Pathway interactions; Pattern; Play; Pregnancy; Principal Investigator; Process; Progesterone Receptors; Program Research Project Grants; Protein Biosynthesis; Proteins; Proteomics; Publishing; RNA Interference; Regulation; Regulator Genes; Research Personnel; Role; STAT5A gene; Sampling; Secretory Cell; Signal Pathway; Signal Transduction; Signaling Molecule; Somatomedins; Stimulus; Technology; Testing; Transgenic Mice; Transgenic Organisms; Woman; base; design; diabetic; fatty acid biosynthesis; glucose transport; improved; in vivo; lipid biosynthesis; mammary epithelium; mammary gland development; monolayer; non-genomic; offspring; pregnant; protein metabolite; pup; receptor

The differentiation of mammary epithelial cells into secretory cells capable of sustaining lactation is of great mportance to newborn health. Secretory activation occurs at parturition, marks the transition between late pregnancy and lactation, and is dependent on Akt. Since diseases such as diabetes and obesity are correlated with Aktl activity and adversely effect lactation. Understanding how Akt functions normally during secretory activation will provide the means to understand lactation defects resulting from these disorders. Much of the molecular analysis of events that underlie this transition has focused upon the regulation of milk protein gene expression. However, milk fat provides the crucial nutrient that supports both growth and brain development of the offspring. Akt dependent metabolic changes that occur at secretory activation include increased glucose transport and elevated lipogenesis that maintain a constant fat composition in milk. We hypothesize that Aktl is a critical genetic regulator of secretory activation that is particularly important in the metabolic switch that occurs at this transition. Three specific aims are designed to test this hypothesis: 1) We will identify genes specific to the mammary epithelium whose expression is regulated by Aktl during secretory differentiation and activation using qPCR and global expression arrays. 2) We will test these Akt dependent regulators for ability to restore lipogenic differentiation and secretory activation in established mammary epithelial cell lines in vitro and in Aktl null mammary epithelium in vivo. We will determine whether any of these genes can stimulate fatty acid biosynthesis to form cytoplasmic lipid droplets in the absence of differentiation stimuli. 3) We will identify mammary epithelium specific phosphorylated protein substrates for Aktl that are necessary for lipogenic differentiation and secretory activation by using multiple proteomic platforms that identify phosphorylated proteins. Cumulatively, the identification of Aktl dependent genes, plus Aktl dependent protein substrates, will allow us to elucidate normal mammary epithelium function of Aktl. We ultimately will provide a strong foundation toward enhancing the impaired lactation of women who are afflicted by diabetes and/or obesity. RELEVANCE (See instructions): Aktl regulates lipogenic differentiation of mammary epithelial cells during pregnancy and lactation; however, it also integrates signals for cell survival, proliferation, and energy metabolism. Because Aktl is activated by diabetes and obesity, it integrates both normal and abnormal stimuli to modulate mammary gland function. Understanding how Akt functions may improve lactation in obese and diabetic women.

乳腺上皮细胞向分泌细胞的分化对维持泌乳具有重要意义 对新生儿健康的重要性。分泌激活发生在分娩时，标志着晚期 妊娠和哺乳，并依赖于Akt。由于糖尿病和肥胖等疾病是 与Aktl活性相关并对泌乳产生不利影响。了解Akt如何正常工作， 分泌激活将提供理解由这些疾病引起的泌乳缺陷的手段。 对这一转变背后的事件的分子分析大多集中在对牛奶的调节上 蛋白基因表达然而，乳脂提供了支持生长和大脑的关键营养素 后代的发展。Akt依赖的代谢变化发生在分泌激活，包括 增加葡萄糖转运和增加脂肪生成，从而维持牛奶中脂肪组成的恒定。我们 假设Aktl是分泌激活的关键遗传调节因子，其在 在这种转变中发生的代谢转换。三个具体的目标是为了测试这一假设：1）我们 将鉴定乳腺上皮特异性的基因，其表达受Aktl的调节， 使用qPCR和全局表达阵列进行分泌分化和激活。2)我们将测试这些Akt 在已建立的细胞中恢复脂肪生成分化和分泌激活能力的依赖性调节因子 在体外的乳腺上皮细胞系中和在体内的Aktl缺失乳腺上皮中。我们将决定 这些基因中的任何一种都可以在缺乏 分化刺激3)我们将鉴定乳腺上皮特异性磷酸化蛋白底物， 利用多蛋白质组学方法研究脂肪生成分化和分泌激活所必需的Aktl 识别磷酸化蛋白的平台。累积起来，Aktl依赖性基因的鉴定， 加上Aktl依赖性蛋白底物，将使我们能够阐明正常乳腺上皮细胞的功能， Aktl我们最终将提供一个坚实的基础，以提高妇女的哺乳受损， 患有糖尿病和/或肥胖症。 相关性（参见说明）： Aktl在妊娠和哺乳期间调节乳腺上皮细胞的脂肪生成分化;然而， 它还整合了细胞存活、增殖和能量代谢的信号。因为Aktl是由 糖尿病和肥胖症，它整合了正常和异常刺激来调节乳腺功能。 了解Akt的功能可能会改善肥胖和糖尿病女性的泌乳。