Rachel Lennon, MBBS, PhD
Professor of Nephrology at the University of Manchester and a Consultant Paediatric Nephrologist at the Royal Manchester Children’s Hospital, UK.
The research in my group is focused on understanding mechanisms of glomerular disease, the leading cause of chronic kidney disease in adults and children since there is a massive unmet need to improve early detection and targeted treatment. The glomerular capillary wall is a highly sophisticated filtration barrier that comprises specialised endothelial cells, the glomerular basement membrane and specialised epithelial cells known as podocytes. Basement membrane regulation is fundamentally required for barrier integrity and we have developed proteomic methods to resolve the cell adhesion-matrix interface and have interrogated ultrastructure using volume scanning electron microscopy. Using a combination of in vitro systems (glomerular cell coculture, kidney organoids) and animal models (mouse, zebrafish) we now seek to understand mechanisms of glomerular barrier injury and repair.
Abstract: Linking basement membrane biology to human genetic variation and disease.
Basement membranes (BMs) are essential for tissue formation and function. Thin and dense structural scaffolds, BMs underlie and support all continuous layers of cells. Core components include laminins and collagens and with proteomic studies we have shown profound molecular complexity with over 100 components expressed in a tissue specific manner. Genetic defects in core BM components cause a spectrum of rare human diseases such as Alport syndrome however, large-scale genetic studies have shown that variants in these core genes are associated with more prevalent human diseases including diabetic kidney disease, haemorrhagic stroke and cardiovascular disease, which affect up to 1 in 3 of the population. We recently curated 225 human genes that localise to BMs, discovered new regulatory components and identified loss of function variants in a wide spectrum of rare human disease within the 100,000 genomes project. I will describe this study during the talk and introduce the tools we have created to investigate BM function, with a particular focus on the kidney.