Funded Research

In the diabetic kidney, a build up of fibrotic material in the proximal region of the nephron, in part, mediates both structural and functional damage culminating in loss of both cell integrity and function. Damage occurs when cells fail to respond as they should, and thus start behaving more characteristic of cells of another tissue type. In doing so, cells lose their ability to synchronize their activity with neighbouring cells. They become less able to directly adhere to surrounding cells and to the extracellular matrix; a skeleton, which surrounds and supports the cell. Loss of these interactions results in failure of transmission of cell survival signals. To date we know little of how high levels of glucose disrupts, both cell structure and function in the proximal nephron. The current proposal will utilize healthy and diseased proximal tubule cells to establish how high glucose and downstream fibrotic Transforming Growth Factor Beta both regulate and disrupt cell-cell and cell-ECM interactions. The aim of these studies is to identify a future therapeutic target for alleviating renal fibrosis in diabetes.

We know that molecules that alter vascular remodelling and vascular growth have been proposed as a treatment for diabetic nephropathy. We have begun to investigate a molecule, which protects the vasculature from injury, called Nogo-B in diabetic kidney disease. We have shown that Nogo-B is found in the kidney glomeruli, and that its levels are reduced in animals with diabetic kidney disease. In this project, we will perform experiments to investigate the role of Nogo-B in diabetic kidney disease. We will study experimental animal models of diabetes in conditions of altered expression of Nogo-B. By modulating Nogo-B levels in the kidney, we will examine whether changes in Nogo-B expression confer a protection (or promote disease susceptibility). If successful, this will open for further studies on the potential targeting of Nogo-B as treatment for diabetic nephropathy.

People with diabetes have impaired formation of new blood vessels in the heart, legs, and other parts of the body. This is an important reason for some complications of diabetes. We have found that insulin can suppress a protein called CITED2 that has a role in limiting blood vessel growth. Therefore, increased levels of CITED2 may suppress blood vessel growth in people with type 2 diabetes in whom insulin has lost its normal effect (a condition called insulin resistance). The research proposed here aims to determine how the CITED2 gene is regulated by insulin. Furthermore, we plan to use mice with poor blood vessel formation due to insulin resistance. We want to show that we can improve blood vessel growth in these mice if we remove the CITED2 gene in vascular cells. Results from this research may indicate that CITED2 could be a future drug target for preventing diabetes complications.