Prof M Wakelam
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Please click on the Babraham Graduate Programme button above for details of how to apply for this project.
Autotaxin (ATX) is a lysophospholipase that catalyses the extracellular hydrolysis of lysophosphatidylcholine to generate lysophosphatidic acid (LPA). LPA acts as an agonist for a family of 6 G-protein coupled cell surface receptors regulating physiological functions such as migration, contraction, apoptosis, proliferation and HCV and HBV infection of liver cells through regulating signalling pathways including PI3kinase, phospholipase C and adenylyl cyclase. Notably ATX and LPA are important constituents of foetal calf and other cell culture sera. The ability of LPA to activate cells is tempered by cell surface lipid phosphate phosphatases (LPP) that rapidly degrade LPA.
Work from a number of labs has demonstrated that LPA can remain bound to ATX following catalytic generation. We have recently demonstrated that a fraction of cell secreted ATX is bound to exosomes released from cells and that this provides a delivery mechanism bringing ATX adjacent to LPA receptors and in an ill-defined manner releasing the LPA to bind to and activate the receptor. This LPA protective delivery mechanism also highlights the potential for intercellular signalling.
The importance of ATX and LPA signalling in physiology and pathology led to the generation of inhibitors in the pathway. CRT have generated a novel series of ATX inhibitors that bind both the acyl chain pocket and the LPA exit channel. The company has the capability to study ATX at the structural level and thus bringing together their skills and the cell and molecular biology capability of the Wakelam lab on the Babraham Research Campus generates an outstanding training opportunity.
In this project the student will determine:
(i) How ATX binds to exosomes and its regulation, preliminary proteomic data suggests the involvement of the matrix proteins agrin, laminins and nidogen-1;
(ii) The mechanism whereby exosomal-ATX interacts with cells to deliver LPA to the cell surface receptors;
(iii) Using structural techniques examine if binding of ATX to exosomes affects catalytic activity, LPC substrate specificity, ability of ATX inhibitors to bind and regulate activity, the mechanism of LPA release;
(iv) Whether the exosome–ATX binding and LPA receptor activation promotes exosome internalisation and thereby inter-cellular delivery of mRNA and microRNA resulting in cellular regulation.
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