About the Project
In early development, a fertilized zygote proceeds through a series of steps to develop into a multicellular blastocyst. The cells of the blastocyst are capable of generating all adult cell types, a phenomenon known as pluripotency. The inner cell mass (ICM) of the blastocyst can moreover be cultured in vitro as pluripotent embryonic stem cells (ESCs), which have become valuable tools for understanding development and regenerative medicine. Since many pathways active during development are hijacked by cancer cells, their study has also given us insight into important processes in cancer.
Recently, it has become clear that major metabolic changes take place during different stages of early embryo development, and that these metabolic shifts may play an important role in driving the epigenetic rewiring that determines pluripotency. How these metabolic changes are regulated, however, is still unclear. Since polar metabolites are not membrane permeable, membrane transporters are essential to regulate both their uptake and release across the plasma membrane, and also their transfer between different cellular compartments. With more than 400 solute carrier (SLC) transporters encoded within the genome, different cell types are able to tailor their transporter expression patterns to shape metabolism according to their functional requirements.
The goal of this project is to uncover how the expression of SLC family transporters changes during the initial stages of early development, and to determine how these expression patterns influence the metabolic changes taking place during development. We employ a combination of candidate and genome-wide approaches in mouse and human ESCs, CRISPRi/a technology, bioinformatics, high-resolution imaging and molecular embryology. These techniques are combined with state-of-the-art metabolomics and stable isotope labelling to permit sensitive analysis of metabolic changes that underlie distinct stages of development.
The successful PhD student will model distinct pre- and peri-implantation stages of development in culture using established mouse and human ESC lines and culture conditions, and employ GC-MS metabolomics combined with stable isotope labelling to observe the metabolic differences between these stages. Based on bioinformatic analysis of transporter expression patterns, they will use CRISPR/Cas9 technology to perturb the expression of key transporters-of-interest, and combine this with pharmacological approaches to investigate their role in development and pluripotency. The student will benefit from the complementary expertise of two labs within the LMS and will be welcomed as a fully integrated member of both groups. These studies will shed light on the importance of SLC proteins and SLC-driven metabolic changes in early development, and may inform our understanding of their roles in pathophysiological contexts such as cancer.
Whilst this funding is available to students worldwide, due to the higher tuition fee rate of overseas students competition is higher and so only exceptional OS applicants will be considered.
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