Research Project
6645356
Advanced stage diabetes is associated with both microvascular and macrovascular changes leading to damage in the kidneys, eyes, and peripheral nerves as well as other cardiovascular disorders. Although the mechanisms behind the diabetes related vascular changes are incompletely understood, the oxidative glycation process is clearly associated with vascular damage. Accumulating new research suggests that the deamination of substrates, such as aminoacetone and methylamine, by semicarbazide-sensitive amine oxidase (SSAO) produces substances (aldehyde, ammonium, and hydrogen peroxide) that can directly cause endothelial cytotoxicity and enhance the formation of advanced glycation end products. In human diabetes and in animal models of diabetes the plasma levels of SSAO are increased, and in diabetic patients a significant positive correlation between SSAO activity and the degree of vascular damage (e.g. nephropathy and retinopathy) exists. The discovery of SSAO activity in the recently characterized and cloned human and mouse vascular adhesion protein-1 (VAP-1) now presents an opportunity to test SSAO biological function with controlled experiments. By using VAP-1 transgenic, VAP-1 knockout, and diabetic mice, both gain of function and loss of function experiments are planned to investigate the relationship between SSAO activity and vascular pathology. Using these mouse models, the release of soluble VAP-1 will also be investigated. Together with specific inhibitors of VAP-1, these mice will be used as models to aid in the assessment of various vascular pathology treatment modalities.
