Characterisation of Novel AGE Binding Proteins: Implications for Diabetic Vascular Complications.

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This project will explore a process known as advanced glycation and in particular how this may lead to organ injury in diabetes. Diabetes is characterised by sustained elevation of blood glucose levels which interact with proteins to generate products known as advanced glycation end-products (AGEs). These AGEs bind to other proteins some of which have been isolated and are considered receptors. Our own group has identified a new family of proteins known as ERM proteins which bind to AGEs. This is a highly novel finding which now needs to be examined in more detail. The ERM proteins which include ezrin, radixin and moiesin are found at many sites of diabetic complications including the kidney, retina and blood vessel wall. They have a number of functions including effects on cell adhesion and cell structure. This is important in diabetes where changes in cells including altered structure have been observed. This grant will characterise the interactions between AGEs and ERM proteins at the molecular and cellular level. It will define how AGEs influence cells via interactions with ERM proteins. These studies have the potential to lead to treatments that may modulate the AGE-ERM interactions, thereby retarding or preventing diabetic vascular complications. These complications are of important clinical significance since they are the major cause of morbidity and mortality in the diabetic population. Furthermore, diabetes is a major cause of premature atherosclerosis in our community, diabetic kidney disease is the leading cause of end-stage renal failure in the Western world and diabetic retinopathy (eye disease) is the main cause of blindness in the working age population.