BBSRC DTP CASE project: Predicting clinical renal drug clearance and potential pharmacokinetic drug-drug interactions using a kidney on a Chip Model

Limited research has been carried out on in vitro renal cellular tools in conjunction with systems biology modelling in order to predict the renal contribution to the pharmacokinetics (PK) of a drug. Currently, renal drug clearance is predicted in human by carrying out invasive PK studies in animals and investigating whether an empirical relationship exists between the different species. In many cases an empirical relationship is not established due to species differences in transporter activity and the prediction of the renal contribution to the PK of a drug for a target species becomes uncertain. In addition to the prediction of renal drug clearance, an established renal in vitro cellular set of tools in conjunction with systems biology modelling would allow the prediction of renal drug-drug interactions.

The objectives of the PhD are to develop primary proximal cell (PTC) and distal tubular cell (DTC) cultures with an organ on a chip system using kidney tissue. Transporter (OATs, OCTs, MRPs, MDR1) protein levels will be assessed by mRNA, immunocytochemistry and western blotting. The kinetic activity of drugs known to undergo renal clearance will be measured using HPLC-MS/MS. Known drug transporter inhibitors will be investigated in the presence of the renally cleared drugs and IC50s determined. Systems biology models using mathematical and kinetic modelling software in conjunction with the organ on a chip kinetic data will be built to model and validate a) the effect of pressure change on transporter function b) predict existing clinical renal clearance data and c) predict known clinical renal drug-drug interactions for marketed drugs.

The project will be supervised by Dr Stuart Paine (School of Veterinary Medicine and Science) and Prof David Gardener (School of Veterinary Medicine and Science).

Entry Requirements
Applicants should have, or expect to achieve, at least a 2:1 Honours degree (or equivalent). The project would suit someone with a background in bioscience, chemistry, medicine, pharmacy, pharmacology or veterinary medicine. The student will join a vibrant and world class interdisciplinary research team, including pharmacists, scientists, and cell biologists.

Studentship information
It is fully funded for four years. The award would be fees (£4409 p.a.) plus an annual stipend (£15,285 p.a. for Oct 2020), set by the Research Councils. A higher rate stipend is available to students with a recognised veterinary degree qualification; for 2020 this is £23,590.

How to apply
This 4-year PhD studentship will be filled as soon as a suitable candidate has been found, candidates are therefore encouraged to apply via https://www.nottingham.ac.uk/bbdtp/apply/apply-online.aspx as soon as possible.

This fully-funded studentship is available to UK students and EU students who have lived in the UK for 3 years prior to the start of their studies. EU students who do not meet this criteria are eligible for a fees-only award.

Prospective applicants are encouraged to contact [Email Address Removed] for more details about the project or visiting https://www.nottingham.ac.uk/bbdtp/case-2020/case-2020.aspx

Closing date: noon, Tuesday 14 July 2020

The start date is 1 October 2020.

Eligibility
This fully-funded studentship is available to UK students and EU students who have lived in the UK for 3 years prior to the start of their studies. EU students without meeting this criteria are eligible for a fees-only award.