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Development of an isolated glomerular albumin permeability assay to high throughput for drug screening in human glomerular disease


Bristol Medical School

About the Project

Rationale
There is an urgent need to identify new clinical treatments for those with kidney disease. It is also critical to have a screening system to enable us to identify novel drugs that are relevant to humans. The ability to measure glomerular permeability is essential in the detection and assessment of glomerular disease. Albuminuria is the standard measure; however, it does not accurately reflect glomerular permeability. This is due to confounding changes in local haemodynamics, as well as tubular reabsorption of filtered albumin. For experimental studies of human glomerular permeability, measurements of albuminuria are not possible. Therefore, we developed a reliable and physiologically relevant assay, recently published, (1) to directly measure glomerular albumin permeability (Ps’alb) using isolated human (and rodent) glomeruli. This allows us to sensitively investigate changes in albumin filtration for the first time in human glomeruli. However, this system is currently laborious and technically challenging and requires development to increase throughput of data.

Aims and objectives
The aim of this studentship is to develop this assay so that it has higher throughput and is technically easier to use. This is to improve the quantify of data whilst maintaining a high quality. Ultimately this will accelerate the repurposing of existing agents and discovery of novel compounds to treat glomerular diseases.

Aim 1: To modify the Ps’alb assay using acoustic force technology
Aim 2: To demonstrate that therapeutic effects on diseased glomeruli can be studied.
Aim 3. To demonstrate that human glomeruli disease models can be used to screen for new therapeutics.

Methodology
The PhD student will gain technical knowledge in confocal microscopy and acoustic force and will help to optimise conditions for data collection. They will acquire knowledge of glomerular physiology in health and disease and work with experimental animal models. The student will use the developed assay to screen for drugs that could be repurposed for glomerular disease.

References

1. Desideri S, Onions KL, Qiu Y, Ramnath RD, Butler MJ, Neal CR, King MLR, Salmon AE, Saleem MA, Welsh GI, Michel CC, Satchell SC, Salmon AHJ, Foster RR: A novel assay provides sensitive measurement of physiologically relevant changes in albumin permeability in isolated human and rodent glomeruli. Kidney Int 2018.

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