Prof G Bou-Gharios
Prof LR Ranganath
Prof J A Gallagher
No more applications being accepted
Funded PhD Project (UK Students Only)
Alkaptonuria (AKU) is an ultrarare disease with prevalence in most populations between 1 in 250,000 to 1 in 1,000,000. AKU is a disorder of tyrosine metabolism in which degradation of tyrosine is blocked at the level of homogentisic acid due to congenital lack of homogentisate dioxygenase enzyme. The manifestations of AKU are multiple and largely due to consequences of high HGA. Although AKU is present from birth, morbidity is typically delayed into the second and third decades of life. However, in renal failure morbidity progresses very rapidly and it is clear that the kidney plays a crucial role. We have recently generated a new conditional animal model for alkaptonuria (Hughes et al 2019). We need to investigate the role of the kidney, which has not been specifically studied in AKU. In particular the handling of HGA by the kidney has not been fully clarified. By identifying the transporter, we may be able to increase HGA excretion and provide a possible cure. Moreover, HGA metabolism is not fully understood. It is possible to collect renal tubular cells from the urine of AKU and non-AKU patients to study their role in HGA metabolism.
Such a collection system exists at the Royal Liverpool University Hospital. More than 70 AKU patients attend the RLUH annually. Despite the introduction of nitisinone, which is highly efficacious in terms of its metabolic effect as it decreases HGA, nitisinone also causes undesirable increases in circulating tyrosine. The role of the kidney in tyrosine handling post-nitisinone needs to be better understood including the transporters involved. Moreover, the dietary variation between patients and non-adherence to dietary regime makes it very difficult to compare therapies and improve outcome. The aim of this project is to understand the role of the kidney in the metabolism of homogentisic acid, tyrosine and phenylalanine.
This studentship will investigate the role of the kidney from the data and samples collected (and to be collected) in the National Alkaptonuria Centre in RLUH. The role of transporters through tissue expression in the kidney cells will be clarified. Moreover, the PhD will also manipulate the expression of collectrin (Tmem27), a relatively short type I transmembrane protein (25 kD) that appear to stabilizes the transporters and allows its transfer to the luminal brush border membrane. The work will mainly use in vitro analysis of proximal tubular cells and biochemical and molecular analysis of modified renal amino acid transporters. In due course this work may move in vivo models and ultimately to man.
Any specific eligibility requirements: We are seeking applications from candidates with a first or upper second class honours degree in a relevant subject, including graduates in biological or biochemical sciences with an interest in translational research. Previous experience in kidney transporters would be advantageous.
The Institute of Ageing and Chronic Disease is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring the Athena SWAN principles are embedded in its activities and strategic initiatives.
Request for further information and applications including CV and the names of two referees should be addressed by email to Professor George Bou-Gharios: [Email Address Removed]
The award covers:
• University fees for 3 years at UK or EU postgraduate student rates (NOT Overseas), £4,327 for 2019 - 20
• Student stipend for 3 years at the recommended UKRI rate, £15,009 for 2019 – 20
• Research costs to cover the whole 3 year period of the study
Hughes JH, Liu K, Plagge A, Wilson PJM, Sutherland H, Norman BP, Hughes AT, Keenan CM, Milan AM, Sakai T, Ranganath LR, Gallagher JA, Bou-Gharios G. Conditional targeting in mice reveals that hepatic homogentisate 1,2-dioxygenase activity is essential in reducing circulating homogentisic acid and for effective therapy in the genetic disease alkaptonuria. Hum Mol Genet. 2019 Oct 10. pii:ddz234.
Hughes JH, Wilson PJM, Sutherland H, Judd S, Hughes AT, Milan AM, Jarvis JC, Bou-Gharios G, Ranganath LR, Gallagher JA. Dietary restriction of tyrosine and phenylalanine lowers tyrosinaemia associated with nitisinone therapy of alkaptonuria. J Inherit Metab Dis. 2019 Sep 10. ahead of print] PubMed PMID: 31503358
Preston AJ, Keenan CM, Sutherland H, Wilson PJ, Wlodarski B, Taylor AM, Williams DP, Ranganath LR, Gallagher JA, Jarvis JC. Ochronotic osteoarthropathy in a mouse model of alkaptonuria, and its inhibition by nitisinone. Ann Rheum Dis. 2014 Jan;73(1):284-9.