Regulation of Cellular Energy Metabolism in Mammary Epithelial Cells

乳腺上皮细胞细胞能量代谢的调节

• 批准号: RGPIN-2019-04740
• 负责人: AudetWalsh, Etienne
• 金额: $ 2.7万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=687001
• 关键词: Regulation; Cellular; Energy; Metabolism; Mammary

The mammary gland is unique to mammals and is essential for milk production that is, following pregnancy, an important metabolic demand for the mother. As such, mammary epithelial cells undergo a metabolic reprogramming that is still poorly understood. During the first five years of my program my goal is to identify the various regulatory pathways that control mammary epithelial cell metabolism and thus establish the foundations of a long-term research program to study the metabolic functions of the mammary gland in vitro and in vivo in diverse mammal species.******First, I will focus on the AMPK and mTOR signalling pathways, two well-known regulatory nodes that govern cellular metabolism. To do so, we will perform signalling studies to establish how these two pathways are activated and inactivated in mammary epithelial cells following nutritional status. Next, we will use state-of-the-art metabolomics approaches to define how AMPK and mTOR control mammary epithelial cell metabolism. This will represent the first study to decipher their precise functions in the unique context of the mammary gland.******Secondly, the mammary gland is also known to be one of the most sensitive organs to endocrine disrupters. These chemicals are often found at biologically relevant concentrations in the environment and interfere with endogenous endocrine signalling, particularly affecting the mammary gland development and functions. However, how these endocrine disrupters modulate mammary epithelial cell metabolism as yet to be defined and this represents our second research axis.******Overall, our work will represent one of the very first studies on the various signallings that govern mammary epithelial cell metabolism. Altogether, the proposed experiments will help us understand the unique regulatory mechanisms that allow the establishment mammary epithelial cell metabolic program to sustain lactation in mammals and how nutritional and environmental exposures affect this program. My long-term objectives following these initial but essential studies are to 1) define new paradigms in cell signalling and cell metabolism and 2) apply this knowledge in vivo to elucidate how these regulatory pathways regulate milk production and composition. Thus, this work will not only represent a breakthrough in the understanding of the metabolic biology of the mammary gland, but will also lead to the identification of the key factors involved in milk composition and production. *****

乳腺对哺乳动物来说是独一无二的，对哺乳动物来说是必不可少的，在怀孕后，哺乳动物对母亲来说是一个重要的代谢需求。因此，乳腺上皮细胞经历的代谢重编程仍然知之甚少。在我项目的前五年，我的目标是确定控制乳腺上皮细胞代谢的各种调节途径，从而为长期研究项目奠定基础，研究乳腺在体外和体内不同哺乳动物物种的代谢功能。******首先，我将重点关注AMPK和mTOR信号通路，这两个众所周知的调控细胞代谢的调控节点。为此，我们将进行信号研究，以确定营养状态下乳腺上皮细胞中这两种途径是如何激活和失活的。接下来，我们将使用最先进的代谢组学方法来定义AMPK和mTOR如何控制乳腺上皮细胞代谢。这将是第一个在乳腺的独特背景下破译它们精确功能的研究。******其次，乳腺也是对内分泌干扰物最敏感的器官之一。这些化学物质通常在环境中以生物学相关的浓度存在，并干扰内源性内分泌信号，特别是影响乳腺的发育和功能。然而，这些内分泌干扰物如何调节乳腺上皮细胞代谢尚不清楚，这是我们的第二个研究方向。******总的来说，我们的工作将是对控制乳腺上皮细胞代谢的各种信号的最早研究之一。总之，本实验将帮助我们了解哺乳动物乳腺上皮细胞代谢程序维持泌乳的独特调控机制，以及营养和环境暴露如何影响该程序。在这些初步但重要的研究之后，我的长期目标是：1)定义细胞信号传导和细胞代谢的新范式；2)在体内应用这些知识来阐明这些调节途径如何调节牛奶的产生和组成。因此，这项工作不仅代表了对乳腺代谢生物学认识的突破，而且还将导致对乳成分和生产的关键因素的识别。＊＊＊＊＊