Regulation of Cellular Energy Metabolism in Mammary Epithelial Cells

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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.