Interrogation and exploitation of the role of regulatory enzymes during invasive migration
Directed cell migration is critical for normal development and is involved in aberrant processes underlying various neurological disorders and cancer cell metastasis. Whilst much is known about the movement of single cells in simple environments, guidance of cells within intact tissues is still poorly understood at the cellular and molecular level. Better understanding of this process has important potential application to the development of technologies for the treatment of disorders associated with deregulated cell migration.
Through several genome-wide genetic screens, we have identified several key regulatory enzymes with direct human counterparts that are necessary for invasive cell migration in the Drosophila ovary. Several of these genes encode part of a well-characterised network of proteins relaying signals to each other, which is amenable to drug treatment. We want to better understand how this signalling network promotes invasive cell migration in fly ovaries and develop approaches for manipulating the activity of specific regulatory enzymes. Mechanistic insights will also guide studies in mammalian tissue culture cells to test functional conservation and provide the first step towards translating our findings towards clinical application. Approaches that we develop to modify enzyme function could ultimately have applications in preventing the spread of malignant tumours in cancer patients or promoting recovery from neuronal tissue damage.
The student will: use real time imaging to examine the role of regulatory enzymes during different stages of guided migration, from initial polarisation to dynamic collective behaviour in Drosophila; develop genetic and chemical genetic approaches for manipulating gene function to obtain further mechanistic insights; and, examine functional conservation of these mechanisms in human cells.
Techniques to be used include: state-of-the-art Drosophila genetics (FRT/Flp site-directed recombination, Gal4-UAS overexpression); cell biology (immunofluorescence; live imaging); molecular biology and biochemistry (recombinant DNA techniques, immunoprecipitation, Western Blotting); chemical genetics (small-molecule inhibitors and drug-resistant kinase alleles).
The student will be embedded within active research groups conducting lab-based molecular genetics, biochemistry and cell biology research highly relevant to the student’s project. Within the group, several lab members are working on related projects, and adjacent collaborating labs have additional expertise, giving the student access to a large set of other workers to gain advice and intellectual input. This project will expose the student to a wide variety of state-of-the art techniques, including live cell imaging, 3D tissue culture and chemical genetics, which will ensure good career development.
Generic skills training will be provided through weekly lab meetings. These will give the student experience of oral presentation of their work, will expose them to other research methods and systems and broaden their scientific outlook. The student will also be expected to attend other seminar series within Liverpool and present their work at a minimum of one international meeting.
Candidates will need to hold, or expect to hold, a first class (or high II.1) degree and have demonstrated an ability to work in a laboratory environment.
This project is open to applicants who are able to obtain their own funding for tuition fee, consumable laboratory costs and living expenses.
A fees bursary may be available for suitably qualified applicants.
References: Bailey FP, et al. (2014) The resistance tetrad: amino acid hotspots for kinome-wide exploitation of drug-resistant protein kinase alleles. Methods Enzymol. 548:117-46
Herrmann A et al. (2015). Cellular memory of hypoxia elicits neuroblastoma metastasis and enables invasion by non-aggressive neighbouring cells. Oncogenesis. 4:e138
Law A-L, et al. (2013) Lamellipodin and the Scar/WAVE complex cooperate to promote cell migration in vivo. Journal of Cell Biology, 203 (4): 673-89.