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Aquaporin water channels in the bladder urothelium as novel targets for treatment of lower urinary tract pathophysiology

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

About This PhD Project

Project Description

Urinary Incontinence (UI) and nocturia (night time urination) are stigmatized, under-diagnosed and under-treated conditions. One-third of the population in the UK aged >40 have experienced loss of bladder control at some point in their adult lives. The social costs are high and even mild symptoms affect social, sexual, interpersonal and professional function. Therefore, bladder storage disorders constitute major public health problems, comparable with the prevalence of musculo-skeletal disorder in the UK. There is still a major unmet clinical need for better therapies for treatment of these conditions and therefore a clear understanding of the underlying patho-physiological processes is required. Recent studies suggested that the bladder urothelium, which was believed to be a poorly permeable urine-blood-barrier, is indeed able to modify composition and volume of urine. This is supported by the fact that the bladder urothelium expresses the transmembrane water channels (aquaporins). These proteins regulate water movement in various tissues e.g. kidney in response to the hormone vasopressin. Thus, aquaporins are exciting new potential targets for the treatment of UI and nocturia. The aim is to investigate the physiological role of aquaporins and vasopressin receptors in porcine and rat urinary bladders. We have recently developed isolated whole bladder models which have proved to be valuable alternatives to human bladder for elucidating physiological functions (1 &3 see above). We will investigate how age, hydration status and urine osmolarity affect the expression and function of aquaporins and vasopressin receptors in the bladder from young and aged salt-loaded, dehydrated and normal rats . This study will allow us to better understand the bladder function under physiological and pathological conditions and to validate aquaporins as targets for the treatment of UI and nocturia.
This multidisciplinary project involves close collaboration between University of Bristol, Bristol Urological Institute (North Bristol NHS Trust), and the University of the West of England (UWE) thus enhancing links with strategic health, academic partners.
The experiments will be carried out at the Department of Physiology and Pharmacology, University of Bristol under supervision of Mr Marcus Drake, Dr Bahareh Vahabi, and Professor Chris Fry.
In addition to standard University of Bristol (UoB) PhD training/activities, the student will have an excellent opportunity to work with our health (North Bristol NHS Trust), academic (UWE) and industrial partners which will be highly beneficial for the development of students’ network, gaining experience outside UoB and increasing the PhD student’s employability.

When applying please select ’Medicine PhD’ within the Faculty of Health Sciences.

References

Lewis SA. Everything you wanted to know about the bladder epithelium but were afraid to ask. Am J Physiol Renal Physiol. 2000 Jun;278(6):F867-74.
2. Spector DA, Wade JB, Dillow R, Steplock DA, Weinman EJ. Expression, localization, and regulation of aquaporin-1 to -3 in rat urothelia. Am J Physiol Renal Physiol. 2002 Jun;282(6):F1034-42.
3. Hohlbrugger G. Changes of hypo- and hypertonic sodium chloride induced by the rat urinary bladder at various filling stages. Evidence for an increased transurothelial access of urine to detrusor nerve and muscle cells with distension. Eur Urol. 1987;13(1-2):83-9.
4. Negrete HO, Lavelle JP, Berg J, Lewis SA, Zeidel ML. Permeability properties of the intact mammalian bladder epithelium. Am J Physiol. 1996 Oct;271(4 Pt 2):F886-94.
5. Johnson JA, Cavert HM, Lifson N, Visscher MB. Permeability of the bladder to water studied by means of isotopes. Am J Physiol. 1951 Apr 1;165(1):87-92.
6. Verkman AS. Aquaporins at a glance. J Cell Sci. 2011 Jul 1;124(Pt 13):2107-12.
7. Terris J, Ecelbarger CA, Nielsen S, Knepper MA. Long-term regulation of four renal aquaporins in rats. Am J Physiol. 1996 Aug;271(2 Pt 2):F414-22.
8. Rubenwolf PC, Georgopoulos NT, Clements LA, Feather S, Holland P, Thomas DF, et al. Expression and localisation of aquaporin water channels in human urothelium in situ and in vitro. Eur Urol. 2009 Dec;56(6):1013-23.
9. Hays RM, Leaf A. Studies on the movement of water through the isolated toad bladder and its modification by vasopressin. 1962. J Am Soc Nephrol. 1997 Jun;8(6):1005-15.
10. Thibonnier M, Snajdar RM, Rapp JP. Characterization of vasopressin receptors of rat urinary bladder and spleen. Am J Physiol. 1986 Jul;251(1 Pt 2):H115-20.
11. Pisipati S, Hashim H. Vasopressin receptors in voiding dysfunction. Handb Exp Pharmacol. 2011(202):453-83.
12. Parsons BA, Drake MJ, Gammie A, Fry CH, Vahabi B. The validation of a functional, isolated pig bladder model for physiological experimentation. Front Pharmacol. 2012;3:52.
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