Chronic kidney disease (CKD), which is characterised by progressive fibrosis and decline in renal function over time, leads to thousands of premature deaths each year, diminishes quality of life and represents a significant financial burden to healthcare systems. Tubulointerstitial fibrosis is the final common pathway of most progressive renal diseases and effective anti-fibrotic drugs that ameliorate chronic kidney disease (CKD) are lacking.
The aim of the proposed study is to develop, characterize, and validate a novel in vitro 3D human kidney organoid culture system ultimately aimed at screening for compounds capable of modulating the tubulointerstitial microenvironment crosstalk that perpetuates development of fibrosis in CKD.
Kidney organoids will be developed using adult human renal cells combined with hydrogels derived from decellularized adult human kidney extracellular matrix (ECM). Although current ECM hydrogels offer robust mechanical support for in vitro cell culture, they lack the necessary organ-specific biochemical and mechanical cues to promote endogenous cell function. Our hypothesis is that scaffolds composed of native kidney ECM will support more optimal organoid development by providing an organ-specific 3D human renal microenvironment.
Overall Experimental Approach
Adult human kidneys have been decellularised by whole organ perfusion with detergents. Acellular kidney sections will be developed from fibrotic kidneys with chronic allograft nephropathy (CAN) by modifying our well-established protocol for liver decellularization. The kidney ECM scaffolds (both from normal and CAN kidneys) will be analysed to confirm decellularization and evaluate preservation of ECM structure and content. Scaffolds will be developed into hydrogels and seeded with renal cells isolated from normal and fibrotic kidneys, to form renal organoids, and evaluated for cell viability, differentiation and ultrastructure. Organoids will be exposed to known profibrotic and nephrotoxic stimuli to compare the response of normal and fibrotic organoids. The response of organoids will also be compared to known in vivo characteristics. . Once successful organoids have been established these will be used to screen for potential anti-fibrotic compounds.
Based in the Research Department of Surgical Biotechnology, Institute of Immunity & Transplantation, Department of Renal Medicine and Institute for Liver and Digestive Health, University College London, you will have the opportunity to work with leading academics and clinicians in this field. The grant is funded by UCB Biopharma and there will be opportunity for the student to access a wide range of scientific platforms and technologies which complement those offered at UCL. Working closely with UCB Biopharma would enable the student to gain a broader perspective on drug discovery and how research is conducted in the pharmaceutical industry.
Applicants are expected to have obtained at least an upper second-class honours degree (2:1, or equivalent qualification) in a relevant subject. . The candidate would be expected to have an interest in renal pathophysiology and regenerative medicine.
Practical experience in a relevant subject would be an advantage, although is not essential.
Eligibility criteria for UCL research degrees can be found at: https://www.ucl.ac.uk/prospective-students/graduate/research-degrees/entry-requirements
This funding is limited to UK/EU nationals. Please note applications from candidates who are not eligible will not be considered.
To apply, please email your CV (including names and contact details of 2 referees), a covering letter describing your research interests and research experience (include examples of previous project work) to: Mr Reza Motallebzadeh ([email protected]
) quoting the job reference 1823965.