Dr J Barber, Prof A Rostami
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
The blood-brain barrier tightly regulates the exchange of molecules between the blood and the brain. Small lipophilic molecules (eg O2 and CO2) easily diffuse through the BBB but carrier-mediated transport allows the access of nutrients (eg glucose and amino acids) and receptor-mediated transport facilitates the uptake of larger molecules including insulin, leptin, and iron transferrin. Brain endothelial cells also efflux certain substances through efflux transporters back in to the blood circulation [1].
ATP-binding cassette and solute carrier transporters (SLC) are the main type of transporters expressed in the brain endothelial cells and are responsible for influx and efflux of drugs across the BBB. [2-4]. The abundance and activity of these transporters in an individual crucially affects whether a drug acting on the brain will be efficacious or cause adverse drug interactions. Transporters are present at low abundance and are membrane-bound, so are notoriously difficult to quantify. Recent developments in mass spectrometry mean that, for the first time, it is possible to quantify the transporters and to assess the extent of inter-individual variation in disease and health. This information can be used in predictive models to estimate drug doses, maximising efficacy and minimising toxicity (and cost).
We aim to identify and quantify the transporters and other proteins relevant for drug and metabolite disposition of the human blood-brain barrier, comparing healthy subjects with subjects with Alzheimer’s Disease. By using a panel of diseased and healthy brains, we will achieve insights into inter-individual variation in transporter abundance, as well as monitoring any gross difference between health and disease. Comparator rat data will also be collected.
Finally we will use the data generated to develop in silico physiological models of drug transport across the BBB in humans and rats, allowing doses of drugs to be estimated in both species without the need for extensive preliminary experiments. The brain model is novel and is therefore of interest to simulators, and will be made available to the drug development community. The rat model (for which no rat will be killed) is required because animal testing of new drugs is a legal requirement; however, an accurate estimate of the dose required for rats will lead to reduction in rat use, as will an understanding of the scaling factors required to convert the rat model into a human model.
Funding Notes
This is a fully-funded studentship through the EPSRC DTP for 3.5 years, commencing September 2017. Applicants must be from the UK/EU and have obtained (or be about to obtain) a minimum 2:1 Bachelors degree in a relevant subject area. Applications should be submitted online, select PhD Pharmacy and Pharmaceutical Sciences on the application form. Interviews will be held in Manchester in May 2017. For informal enquiries, please contact Dr Jill Barber ([Email Address Removed]) or Professor Amin Rostami ([Email Address Removed]).
References
1] Zheng W, Aschner M, Ghersi-Egea J-F. Brain barrier systems: a new frontier in metal neurotoxicological research. Toxicol Appl Pharmacol 2003;192:1–11. doi:10.1016/S0041-008X(03)00251-5.
[2] Uchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, et al. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem 2011;117:333–45. doi:10.1111/j.1471-4159.2011.07208.x.
[3] Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: An overview. Adv Drug Deliv Rev 2012;64:138–53. doi:10.1016/j.addr.2012.09.027.
[4] Golden PL, Pollack GM. Blood-brain barrier efflux transport. J Pharm Sci 2003;92:1739–53. doi:10.1002/jps.10424.