Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2022 and will register for their PhD at one of the Crick partner universities (Imperial College London).
This 4-year joint Crick PhD studentship is offered in the Group labs of Dr Jean-Paul Vincent and Dr Ben Schumann, based at the Francis Crick Institute (the Crick).
Signalling molecules, such as growth factors and morphogenic proteins, organise tissues and integrate pro-growth signals. The Vincent lab is interested in the processes that ensure the establishment of the right signalling landscape (production and spread of signalling molecules) and how these processes are interpreted to activate the appropriate growth rates and cell fate decision. We use the fly Drosophila melanogaster as a model system that offers the latest methods of molecular genetics and the ability to examine the behaviour of cells within their normal tissue environment. We are using protein engineering as well as state-of-the-art methods of quantitative biology to study signalling pathways, for instance through manipulating growth factor gradients.[1] Our general approach involves merging the power of genome engineering with a variety of techniques borrowed from cell biology, biochemistry, chemistry and physics.
Posttranslational modifications are key mediators of signalling pathways. For instance, the interaction between the growth factors of the Wnt family and their cognate receptors require a palmitoylate moiety for activity. The corresponding deacylase Notum that inactivates Wnt on the cell surface requires heavily glycosylated glypicans to function.[2] Other posttranslational modifications are likely to have similar effects on modulating signalling.
Glycosylation is the most abundant and most complex posttranslational protein modification. The vast majority of all proteins trafficking through the secretory pathway are glycosylated. To individual proteins, glycans add function and alter both physical and biochemical properties. While extremely abundant, particular structural changes in protein glycosylation can profoundly impact the physiological properties as well as interaction with other biomolecules.[3]
Understanding the role of glycosylation in signalling processes is paramount to obtaining a detailed view on evolutionary and developmental processes. However, the nature of glycans as secondary gene products renders them refractory to simple processes of manipulation and sequencing. The Schumann lab is developing tools to chemically modify single monosaccharides – the most basic unit of carbohydrates – and then track how these are incorporated into proteins. Our mission is the generation of so-called “precision tools” that are specific to the activity of certain glycosylating enzymes, glycan subtypes and cell types, to harness the power of quantitative biology instrumentation available at the Crick.[4, 5] We use chemical and chemoenzymatic synthesis to develop such sugars and employ methods of molecular and cell biology to study how they are used to dissect the implications of glycans in health and disease. We collaborate closely with the Crick Science Technology Platforms, in particular the Proteomics STP, to develop new techniques in chemical proteomics to profile glycosylation.
This PhD project will encompass the development and application of chemical precision tools to understand signalling and developmental processes in Drosophila melanogaster. The combination of Drosophila genetics and chemical biology has great potential to accelerate discoveries that are translatable to human health and disease.
Candidate background
The position would be ideal for a biochemist or biologist with an interest in developing techniques to dissect physiological mechanisms of evolution and development in Drosophila melanogaster. The ideal candidate has a background in molecular biology/genetics and some biochemical understanding of the three-dimensional structure of proteins and glycans. Some background in mass spectrometry proteomics or transcriptomics is desirable but not essential. A background in synthetic chemistry is not required for this project.
Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.
APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘INSTITUTION WEBSITE’ LINK ABOVE) BY 12:00 (NOON) 11 November 2021. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.
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