Metabolic interactions between neural stem cells and their niche

A Crick PhD position for the 2021 programme in the lab of Alex Gould.

Project background and description

The growing fetal brain is highly protected against environmental stresses such as malnutrition or hypoxia. This process, known as brain sparing, is a critical survival adaptation that has an important role in safeguarding key aspects of cognitive development. Currently very little is known about the metabolic pathways that drive brain sparing or how they protect neural stem cells and their local microenvironment, the niche. Research in our laboratory aims to discover these metabolic pathways by harnessing advanced genetic methods in the fruit fly Drosophila (http://flybase.org) and then following up key conserved metabolic pathways in mammals.  

Proliferating neural stem cells (called neuroblasts) in the Drosophila CNS are initially sensitive to dietary nutrients [1]. Later in development, however, they transition to a state that is highly resistant to starvation or hypoxic stress - resembling mammalian brain sparing [2, 3]. One project available in our laboratory is to identify the metabolic mechanisms responsible for the stress-resistance of neural stem cells and their niche. This project will utilise a combination of genetics, single cell RNA sequencing (scRNAseq) and metabolomics. It will also take advantage of Cryo-OrbiSIMS, a technique for mass spectrometry imaging that we recently developed. This new method allows a full mass spectrum of metabolites to be imaged in tissues, pixel by pixel, with unprecedented spatial resolution [4, 5]. Successful candidates will have significant input into the design of their project. This is just one of several possible projects in the Gould laboratory (http://www.crick.ac.uk/alex-gould and https://www.agouldlab.com). 

Candidate background

Applications are encouraged from highly motivated candidates with a degree and other relevant experience in molecular biology, bioinformatics, genetics, biochemistry, analytical chemistry or metabolism. Prior experience working with Drosophila is not essential. Advanced training in genetics, cell biology, microscopy, metabolomics and mass spectrometry imaging will be provided.

References

1.    Sousa-Nunes, R., Yee, L.L. and Gould, A.P. (2011)

       Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila.

       Nature 471: 508-512. PubMed abstract

2.    Bailey, A.P., Koster, G., Guillermier, C., Hirst, E.M.A., MacRae, J.I., Lechene, C.P., . . . Gould, A.P. (2015)

       Antioxidant role for lipid droplets in a stem cell niche of Drosophila.

       Cell 163: 340-353. PubMed abstract

3.    Cheng, L.Y., Bailey, A.P., Leevers, S.J., Ragan, T.J., Driscoll, P.C. and Gould, A.P. (2011)

       Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila.

       Cell 146: 435-447. PubMed abstract

4.    Newell, C.L., Vorng, J.-L., Macrae, J.I., Gilmore, I.S. and Gould, A.P. (2020)

       Cryogenic OrbiSIMS localizes semi-volatile molecules in biological tissues.

       Angewandte Chemie International Edition Epub ahead of print. PubMed abstract

5.    Gilmore, I., West, A., Alexander, M. and Gould, A. (2017)

       Principles of Systems Biology, No. 24 : Sub-cellular imaging of metabolites with 3D OrbiSIMS.

       Cell Systems 5: 534. PubMed abstract