Regulation of Cellular Energy Metabolism in Mammary Epithelial Cells

乳腺是哺乳动物所特有的，并且对于乳汁的产生是必不可少的，乳汁的产生是怀孕后母亲的重要代谢需求。因此，乳腺上皮细胞经历代谢重编程，这仍然知之甚少。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控途径，从而建立长期研究计划的基础，以研究不同哺乳动物物种体内和体外乳腺的代谢功能。首先，我将集中在AMPK和mTOR信号通路，两个众所周知的调节节点，管理细胞代谢。为此，我们将进行信号转导研究，以确定这两种途径如何在营养状态下在乳腺上皮细胞中激活和失活。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。这将是第一项在乳腺独特环境中破译其精确功能的研究。其次，乳腺也被认为是对内分泌干扰物最敏感的器官之一。这些化学品在环境中的浓度往往与生物学有关，干扰内源性内分泌信号，特别是影响乳腺发育和功能。然而，这些内分泌干扰物如何调节乳腺上皮细胞代谢尚未确定，这是我们的第二个研究轴。总的来说，我们的工作将代表对乳腺上皮细胞代谢的各种信号的最早研究之一。总之，拟议的实验将帮助我们了解独特的调节机制，使建立乳腺上皮细胞代谢程序，以维持哺乳动物的泌乳，以及如何营养和环境暴露影响这一计划。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）将这些知识应用于体内，以阐明这些调控途径如何调节牛奶的生产和组成。因此，这项工作不仅代表了对乳腺代谢生物学的理解的突破，而且还将导致识别参与牛奶组成和生产的关键因素。

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.