About the Project
The common life-shortening genetic disease cystic fibrosis (CF) is caused by dysfunction of the epithelial Cl- channel cystic fibrosis transmembrane conductance regulator (CFTR). Many individuals living with CF suffer from distal intestinal obstructive syndrome (DIOS). To find new treatments for DIOS, the UK CF charity, the CF Trust, has launched a Strategic Research Centre (SRC), a virtual research centre, focused on intestinal disease in CF. Led by the University of Liverpool, this SRC brings together clinicians and scientists from Liverpool, Bristol, Sheffield, Rotterdam, Hannover and Jerusalem with expertise in CF and the intestine in a multi-disciplinary team.
As part of this SRC, Prof Sheppard (Bristol) and Dr Robson and her colleagues Prof Taylor and Dr Muimo (Sheffield) will supervise a student investigating Cl- channels in the apical membrane of intestinal epithelial cells and the action of drugs designed to restore luminal fluidity to the small intestine in CF. For their research, the student will use intestinal organoids (“mini guts”) generated from small intestinal biopsies from normal subjects and CF patients with and without DIOS. Following training, the student will grow 3-D organoids for confocal imaging studies and 2-D organoids as polarised epithelia for electrophysiological studies.
For further information about Cystic Fibrosis Trust-funded Strategic Research Centres, see:
https://www.cysticfibrosis.org.uk/the-work-we-do/research/research-we-are-funding/strategic-research-centres
For further information about David Sheppard’s research, see:
http://www.bristol.ac.uk/phys-pharm/people/david-n-sheppard/overview.html
For further information about Louise Robson’s research, see:
http://www.sheffield.ac.uk/bms/research/robson#tab00
The student will investigate CFTR as well as other Cl- channels that might compensate for CFTR dysfunction (e.g. TMEM16A) in CF. To examine the role of different types of apical membrane Cl- channel, the student will begin by monitoring the swelling of 3-D organoids treated with Cl- channel activators and inhibitors. Then, they will use 2-D organoids to study transepithelial ion transport with the Ussing chamber technique before using the patch-clamp technique to characterise the single-channel properties of apical membrane Cl- channels. Based on their results, the student will test different drugs on CF intestinal organoids grown in 3-D and 2-D to identify agents that restore luminal fluid to the small intestine in CF. The student’s results will help to inform the selection of a drug for a clinical trial of a new therapy for DIOS.
This SRC is committed to excellent PhD student training to encourage a long-lasting commitment to CF. The student supervised by Prof Sheppard and Dr Robson will receive thorough training in cutting-edge biomedical research methods and excellent generic research training. They will network closely with other trainees in the SRC, visit different laboratories to develop research skills and present their work at international scientific conferences. Thus, through this project the student will gain exceptional research training and generate important new knowledge about the CF intestine to inform the development of rational new therapies for intestinal disease in CF.
Informal enquiries to: Prof David N. Sheppard, School of Physiology, Pharmacology and Neuroscience, University of Bristol; Tel: 0117 331 2290; E-mail: [Email Address Removed] and Dr Louise Robson, Department of Biomedical Science, University of Sheffield; Tel: 0114 222 4688; E-mail: [Email Address Removed]
Funding Notes
This is a fully funded 3 Year PhD studentship by Cystic Fibrosis Trust for UK/EU citizens resident in the UK. When applying please ensure that you select the Faculty of Biomedical Sciences, School of Physiology and Pharmacology, PhD 3 year.
Applicants must have a minimum of a 2:1 in their degree or equivalent and and an English Language score of 6.5 overall and in all bands.
References
Dekkers JF, Berkers G, Kruisselbrink E, Vonk A, de Jonge HR, Janssens HM, Bronsveld I, van de Graaf EA, Nieuwenhuis EE, Houwen RH, Vleggaar FP, Escher JC, de Rijke YB, Majoor CJ, Heijerman HG, de Winter-de Groot KM, Clevers H, van der Ent CK, Beekman JM. Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis. Sci Transl Med. 2016; 8:344ra84.
Meng X, Wang Y, Wang X, Wrennall JA, Rimington TL, Li H, Cai Z, Ford RC, Sheppard DN. Two small molecules restore stability to a subpopulation of the cystic fibrosis transmembrane conductance regulator with the predominant disease-causing mutation. J Biol Chem. 2017; 292:3706-3719.
Wang Y, Wrennall JA, Cai Z, Li H, Sheppard DN. Understanding how cystic fibrosis mutations disrupt CFTR function: From single molecules to animal models. Int J Biochem Cell Biol. 2014; 52C:47-57.
Zachos NC, Kovbasnjuk O, Foulke-Abel J, In J, Blutt SE, de Jonge HR, Estes MK, Donowitz M. Human enteroids/colonoids and intestinal organoids functionally recapitulate normal intestinal physiology and pathophysiology. J Biol Chem. 2016; 291:3759-66.
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