An investigation into the genetic and functional basis of proteinuric kidney disease

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Chronic kidney disease affects 13% of the UK population, with 59,000 UK patients either on dialysis or dependent on a kidney transplant for the treatment of kidney failure. Worldwide 1.9 million patients receive these kidney replacement therapies, with many more unable to access these expensive and limited resources. Kidney disease is often associated with abnormal leak of protein into the urine, for example in rare inherited diseases and in diabetes, the leading cause of kidney failure worldwide. This protein leak is due to failure of the filtration barrier, by which healthy kidneys act as selective sieves, filtering waste products and excess water, but keeping important proteins in the blood. Unique cells called podocytes are key component of this barrier, but because they do not replicate and are difficult to alter genetically, podocytes present specific challenges for research. In order to develop more effective, safer treatments, we need to understand more about how damage to podocytes and the filtration barrier leads to protein leak and disease. Genome sequencing projects in patients have begun to reveal many genes associated with a severe protein leak. However, because humans carry many genetic differences from each other it can be difficult to pinpoint which gene from a shortlist of candidates actually causes the disease. The aim of the project is to address this problem, by applying recent advances in techniques to manipulate genes precisely and efficiently. These methods will be used to develop and study models of kidney disease carrying patient mutations. By measuring the effects of gene disruption on cells and organisms, we will identify new disease genes, leading directly to a genetic diagnosis for more patients with rare kidney diseases. This genetic diagnosis can help patients and families, even if it does not immediately change treatment, by quantifying risk in different individuals and helping with planning.The models of human gene variation produced in this project will lead to more detailed study of kidney biology at the level of cells and tissues. One further aim of the project is to explore ways to connect genes to disease, using sequencing techniques to measure the landscape of 'switched on' genes. These techniques will gather and compare information at the level of individual cells and kidney tissues. In the future this approach may have clinical applications in human tissue such as kidney biopsy samples. In the long term, better tools for investigating genetic differences and greater understanding of the effects of mutations on pathways and cellular systems will provide new targets for treating kidney disease, improve outcomes for individuals and reduce the health and economic burdens of chronic kidney disease.