Cystinuria is a debilitating inherited kidney stone disease which commonly results in kidney dysfunction, multiple kidney stone formation and in some patients kidney failure requiring dialysis or a kidney transplant. Unfortunately the currently available treatment options have a number of severe side-effects which limit their use. The molecular basis of cystinuria resides in the proximal tubular epithelial cells of the kidney and their inability to reabsorb Cystine and other dibasic amino-acids from here. This PhD will be based upon a unique proximal tubular human cell line our laboratory (1) has developed and the genetic manipulation of the two major cystine transporters located here called BAT and rBAT. Common mutations that are found in patients (2) will be modelled and functional assays of radioactive cysteine will be developed. Transporter trafficking will be assayed using green and red fluorescent tagged BAT and rBAT constructs and imaging in the state of art Wolfson imaging centre in Bristol University. We will then assess a functional compound library of drugs that target different cellular processes to assess if any of these can rescue specific genetic mutations previously modelled. This project will increase our understanding of the molecular biology of human cellular amino-acid transporters and also potentially reveal new pharmacological classes of drugs that can prevent cystinuria’s severe complications. It has great translational potential to improve people’s lives with cystinuria through a personalized genetic approach.
When applying please select ’Medicine PhD’ within the Faculty of Health Sciences.
(1) Novel conditionally immortalized human proximal tubule cell line expressing functional influx and efflux transporters Wilmer MJ1, Saleem MA, Masereeuw R, Ni L, van der Velden TJ, Russel FG, Mathieson PW, Monnens LA, van den Heuvel LP, Levtchenko EN. Cell Tissue Res. 2010 Feb;339(2):449-57.
(2) Clinical and genetic analysis of patients with cystinuria in the United Kingdom. Rhodes HL, Yarram-Smith L, Rice SJ, Tabaksert A, Edwards N, Hartley A, Woodward MN, Smithson SL, Tomson C, Welsh GI, Williams M, Thwaites DT, Sayer JA, Coward RJ. Clin J Am Soc Nephrol. 2015 Jul 7;10(7):1235-45