Utilising cell penetrating peptides and proteins to regulate cellular lipid content
Applicants (UK, EU and international) capable of self-funding or with scholarship are welcome to apply.
Principal Supervisor: - Dr Pete Watson
Second Supervisor:- Dr Arwyn T Jones (Pharmacy)
Lipid storage mechanisms have evolved to allow animals to survive periods of nutrient deprivation. Excess energy derived from diet is stored as triacylglycerol, which can be efficiently packaged within mammalian cells as lipid droplets. Deregulation of lipid homeostasis is a major contributing factor to many pathological conditions, including atherosclerosis and diabetes. Regaining control of lipid droplet homeostasis is an important step in preventing the onset of these disease states. We have identified a number of proteins that affect lipid droplet formation and regulation, thus suggesting they may have therapeutic potential as lipid modifying agents. Delivering membrane impermeable proteins to cells is however a major challenge and we currently study Cell Penetrating Peptides (CPP) as potential delivery vectors. Supercharged proteins are a new and exciting class of engineered cell vectors that allow transport of potential therapeutics across biological membranes at sub-micro molar concentrations. Using a range of molecular and cell biology techniques this project will develop both CPP and “supercharged protein” entry systems to deliver lipid modifying proteins into cells, thus affecting lipid content. The development of the delivery strategy, along with information on the mechanism of action within the system (from cell entry to effect), will allow the capacity of this approach towards a realistic therapeutic to be determined.
Cronican JJ, Thompson DB, Beier KT, McNaughton BR, Cepko CL, Liu DR. Potent delivery of functional proteins into Mammalian cells in vitro and in vivo using a supercharged protein. ACS Chem Biol. (2010) 5(8):747-52.
Watkins, C., Brennan, P., Fegan, C., Nakase, I., Futaki, S., and Jones, A.T. Cellular uptake, distribution and cytotoxicity of the hydrophobic cell penetrating peptide sequence PFVYLI linked to the proapoptotic domain peptide PAD.J. Control. Release (2009)140(3):237-44