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Treating childhood glomerulosclerosis through angiogenic therapy

Treating childhood glomerulosclerosis through angiogenic therapy to modulate the kidney microvasculature

A 3-year PhD Studentship funded by Kidney Research UK is available in the Kidney Development and Disease group https://www.ich-kidney.co.uk/ within the Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health (UCL GOS ICH). The studentship will commence in spring/summer 2024, under the supervision of Dr Jennie Chandler and Professor David Long.

Background:

Approximately one third of children presenting with steroid-resistant nephrotic syndrome have mutations in genes essential for podocyte health. These children respond poorly to immunosuppressive drugs and develop irreversible glomerular scarring, termed glomerulosclerosis. Therefore, there is a critical clinical need to identify new treatment targets for these patients. Using a preclinical model, we have identified a potential new treatment target for this disease: the kidney microvasculature, comprised of highly specialised blood capillaries and the lymphatics.

Hypothesis/Aims:

The aim of this PhD studentship is to study how the entire renal microvasculature matures in early childhood and how this is altered in disease. From this, the student will investigate the role of a candidate vascular molecule, which our preliminary work has suggested holds therapeutic potential. This will be achieved through an array of cutting-edge techniques, from wholemount tissue clearing and imaging, to 3D in vitro culture technologies and in vivo therapeutic rescue. To achieve this, the student will undertake the following objectives.

Timeline:

Objective 1 (0-12 months): Characterise the postnatal maturation of the kidney microvasculature in health and in disease, prior to and during the onset of glomerulosclerosis, using wholemount immunolabelling and confocal microscopy. The student will assess how maturation of the entire vasculature (capillaries and lymphatics) is impacted in a preclinical mouse model of childhood glomerulosclerosis, as well as human paediatric tissues with and without glomerular disease.

Objective 2 (12-24 months): Investigate the role of a candidate vascular factor in microvasculature health, by performing in vitro stimulation and blockade analyses in key glomerular and lymphatic cell types. The role of this molecule on cellular permeability will be assessed using bespoke 3D in vitro culture technologies.

Objective 3 (24-36 months): Determine the efficacy of the candidate molecule in supporting renal microvasculature health, acting to alleviate disease progression in a preclinical trial in mice. The student will examine how the renal microvascular architecture and function, alongside biomolecular measures of kidney health, are affected by the novel therapy.

Ethics Approval: Ethics is already obtained. The student will be required to secure an animal Licence from the Home Office, if not already held.

Research and Policy outputs:

By the end of this PhD the student will have characterised the kidney vasculature and investigated its potential as a new therapeutic target in childhood glomerulosclerosis. This work will advance new treatment options for a currently untreatable disease.

References:

  1. Chandler et al (2023). Exploration of the single-cell transcriptomic landscape identifies aberrant glomerular cell crosstalk in a murine model of WT1 kidney disease. bioRxiv. 2022: 2022. 10.11. 511555.
  2. Jafree et al (2019). Spatiotemporal dynamics and heterogeneity of renal lymphatics in mammalian development and cystic kidney disease. Elife
  3. Jafree & Long (2020). Beyond a passive conduit: implications of lymphatic biology for kidney diseases. J Am Soc Nephrol. 31, 1178–1190.
  4. Balough & Chandler et al (2020). Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis. PNAS: 117, 15137–15147.
  5. Long et al (2012). Restoring the renal microvasculature to treat chronic kidney disease. Nat Rev Nephrol. 8, 244–250.

Environment:

The student will work within the Kidney Development and Disease Group at the UCL Great Ormond Street Institute of Child Health. This team is a dynamic team of over 20 scientists and clinicians all working towards better healthcare options for children with kidney and bladder disease. We use a combination of preclinical in vivo models and human in vitro models to characterise novel disease pathways and trial candidate therapeutics to alleviate them. A critical aim of our group is to advance renal gene therapies.

The student will learn about all aspects of the proposed methodologies, from the basics of animal husbandry and cell culture to cutting-edge techniques of wholemount immunolabelling and confocal microscopy, 3D image analysis, 3D cell culture technologies and emerging gene therapy approaches to treat glomerular disease.

This Studentship presents a unique opportunity to conduct supervised research at UCL Great Ormond Street Institute of Child Health and be a part of the world-leading research community, being an integral part of the exciting and thriving research team.

About you

Applicants should have a good first degree (UK 1st class or upper 2nd class honours degree or equivalent from abroad) and a Master’s degree (or equivalent work experience) in a relevant discipline by the time of registration.

Eligibilty 

The studentship provides a starting stipend of £20,622 per annum and covers the cost of tuition fees based on the UK (Home) rate. Non-UK students can apply, but if they are not eligible for UK fee status, will have to personally fund the difference between the UK (Home) rate and the Overseas rate.

NB: You will be asked about your likely fee status at the interview so we would advise you to contact the UCL Graduate Admissions Office for advice, should you be unsure whether you meet the eligibility criteria for home fees status. EU nationals should see this Student fee status page for information about eligibility for Home fees. See also the UKCISA website (England: HE fee status).

How to Apply 

To apply, please send a current CV including the contact details of two professional referees as well as a 1-sided A4 cover letter to ich.dbc.admin@ucl.ac.uk. Enquiries regarding the post can be made to Dr Jennie Chandler, j.chandler@ucl.ac.uk

Deadline for receipt of applications: 5pm, Friday 8th March 2024. 

Interview date 19th-21st March 2024 to be confirmed.

Applications that are submitted without following the correct application process will not be considered. The successful applicant will then be required to apply to and register on the Child Health research degree to take up the studentship.