Supported Research

Lay Summary
One of the main roles of the kidney is to filter the blood, removing waste products and toxins. The units responsible for this filtration are called glomeruli, inside which two specialized cell types, the podocytes and the endothelial cells, create a barrier separating the bloodstream from the waste solution which will become urine. When the kidneys are made and the glomeruli develop, a layer of podocyte cells forms on the outside of the blood vessels and a layer of endothelial cells coats the inside. Both cell types then produce a special meshwork of proteins which forms a barrier to prevent important components within the blood from being lost. This barrier is called the glomerular filtration barrier. A tight glomerular filtration barrier is critical to prevent loss of blood cells and proteins.

Alport syndrome is a kidney disease caused by defects in a particular protein which makes up this barrier: collagen IV. These defects cause the barrier to be leaky. As a result, patients lose proteins and even blood through the barrier and into the urine. Different Alport patients have different mutations, hence the severity and onset of their disease can vary. However, we have no treatment for this disease as we are not yet able to understand why the leakiness occurs or how to fix the problem. This is in part because recreating a model of the glomerular filtration barrier in the laboratory is extremely difficult as the podocytes do not function normally when grown in the laboratory. As a result, research into this disease has largely relied on the use of animal models.

In an important breakthrough we have developed a novel method to recreate three dimensional human glomeruli using stem cells. We can create this model from the stem cells of any individual, including Alport disease patients. As a result, we believe this represents a unique way to accurately model the glomeruli of Alport syndrome patients and compare these to the glomeruli of healthy individuals. This will allow us to investigate what is causing the disease patient by patient, potentially allowing us to screen for drug treatments that will work for individual cases.

In this project we aim to investigate the role of both cell types in the glomeruli, the podocytes and the endothelial cells, to the normal form and function of the glomerular filtration barrier in disease by comparing glomeruli made from the stem cells of an Alport patient with an X-linked COL4A5 mutation and their unaffected sibling. This will show whether or not this approach can be used for drug screening.