Cyclin Dependent Kinases As Drug-Targets To Reduce Renal Cyst Formation and Scarring in Polycystic Kidney Disease

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Polcystic kidney disease (PKD) is one of the most common genetic diseases in humans. The most common type (autosomal dominant-PKD) affects approximately 1:400 to 1:1000 individuals worldwide. Kidney failure is the most debilitating and serious complication of PKD, and it accounts for approximately 10% of the cases of end-stage kidney requiring artificial kidney treatment (dialysis) or transplantation. Over the last decade, major advances have been made in preventing kidney failure due to diabetic kidney disease, but these are ineffective for PKD. As such, currently, there is no treatment to prevent kidney failure due to PKD, and new therapies are needed. PKD is characterised by the development of multiple cysts in the kidney, which enlarge and destroy normal kidney tissue. The growth of the cysts is due to uncontrolled growth (cell division) of the cells of the kidney (epithelial cells), which causes cyst formation. In recent years, gene mutations in proteins called polcysytins are thought to be responsible for the cause of the disease. However, the genetic mutations in PKD are complex (>30 types for autosomal dominant PKD alone), and it is unlikely that gene therapy will be possible with current technology in the near future. A simpler approach is to develop 'drugs' that target the consequences of the mutation. This project will investigate the role of a group proteins, called cyclin-dependent kinases (CDKs) in PKD. CDKs which are enzymes that are critical in promoting cell division. Our preliminary data shows that CDKs are upregulated in PKD. The aim of this project is to establish the importance of CDKs in PKD, and examine the effect of new drugs (CDK inhibitors) in maintaining in preventing cyst growth and kidney scarring in PKD. CDK inhibitors are currently being tested in phase 1 and 2 clinical trials in patients with cancer, and this will facilitate the translation of the findings of this project to humans with PKD.