Decoding senescent cell signalling pathways in tissue fibrosis

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Chronic kidney disease (CKD) affects over 700 million people worldwide and is more common in older patients and survivors of previous acute kidney injury. Treatment options are limited, and CKD often progresses despite maximal current medical therapy. There is an unmet need for novel treatments to halt the progressive scarring typical of CKD.My previous work has shown that senescent cells ("SCs" - altered, permanently growth-arrested cells) are present in increased numbers in human CKD, and that in animal models of kidney injury and ageing, the presence of SCs promotes progressive scarring and functional loss. Our studies also showed that treatments that kill senescent cells improve the ability of older and previously damaged kidneys to regenerate after further injuries. I hypothesise that inhibiting signalling pathways in chronic senescent cells (SCs) will provide a more precise way to preserve renal structure and function by preventing their effects on scarring and promoting their clearance. To do this, we will first examine samples of human kidneys with CKD - and use new, high-resolution techniques to explore SC behaviour at single cell resolution - identifying which pathways connect SCs to the production of fibrosis, inflammation and worse long term outcomes.Next, we will dissect out the influence of SC derived pathways on inflammatory cells and on scar producing cells using an advanced 'organ-on-a-chip' cell culture environment which will allow us to tease out exactly which pathways account for the ability of SCs to resist clearance by immune cells, and how SCs directly or indirectly cause fibrosis to be produced in a way not possible in a whole kidney. In collaboration with our colleagues in the Edinburgh Drug Discovery Unit we will then use their expertise to perform highly efficient, automated testing of thousands of potential drug compounds - looking for agents which inhibit the pathways we have identified as causative in our earlier work - and which selectively promote inactivation and/or clearance of SCs without side effects on healthy cells.We will next test the safety and efficacy of treatments designed to prevent SC driven kidney scarring, whilst promoting the healthy clearance of SCs in mouse models of kidney fibrosis. We will use a strain of mouse where SCs can be labelled with two different fluorescent colours, giving us additional information on whether SCs behave differently the longer they persist after initial injury. We will be able to examine the effects of our drugs on SC number and behaviour, as well as immune cell and fibroblast (the type of cell responsible for the production of scarring within the kidney) behaviour, measuring how well each drug protects the function of the kidney after injury. Finally, we will move our work from bench back to human kidneys - which have been offered for transplantation but deemed unsuitable for re-implantation. Using machinery to keep the kidneys alive, warm and oxygenated we will administer and observe the safety and efficacy of our best-performing targeted anti-SC therapy in the human kidney, setting the stage for early translation to clinical studies.