Diabetic Complications

Head – Phillip Kantharidis

Research for this lab focuses on genes that regulate cell growth and differentiation in response to diabetic disease, with a particular focus on kidney disease.

The lab is primarily concerned with the investigation of genes and their products that are altered as a consequence of diabetes, with particular interest in genes that regulate the activity and expression of factors that result in kidney fibrosis, where the tissue becomes scarred and hardened.

Many small and large molecules in our bodies undergo modifications in the context of diabetic disease. DNA is often damaged as a result of oxidative stress in diabetes, resulting in the activation of a number of proteins. One of these proteins, PARP, is known to modify other proteins in the nucleus of the cell in response to DNA damage. While some of the effects of these modifications are known, many are not. Better understanding of these modifications and the protein targets may help to contain diabetic kidney disease and eventually prevent it.

Another project of this group focuses on the response of cells to the diabetic environment. Of particular interest is the activation of key regulatory molecules called transcriptional repressors that control cell differentiation through a process called epithelial to mesenchymal transition (EMT). The lab has demonstrated that this process can occur as a result of high glucose and exposure to advanced glycation end products, influencing the cell phenotype in the kidney and potentially contributing to fibrotic kidney disease. Focusing on the kidney, this team is investigating when these cells change from their original state and start producing things that make the kidney harden and eventually fail. The group hopes eventually to prevent the progression of disease caused by diabetic complications and also prevent the worsening of disease in those already suffering.

The third major interest of the group is the study of proteins called histones, which may be affected by advanced glycation. These proteins form the scaffolding on which DNA is tethered in the nucleus, playing an intricate and extremely important role in regulating which genes are active and which genes get switched off. The focus of this project is to investigate whether modification of histones in the context of diabetes affects their normal nuclear function and hence contributes to diabetic disease.