Gul N. Shah
Ph.D., Pennsylvania State University, PA
Department: Biochemistry and Molecular Biology
Academic Rank: Research Professor
Phone: 314-977-9293 Fax: 314-977-6797
Primary Area of Cardiovascular Research Interest
Biochemical and molecular mechanisms involved in the complications of diabetes mellitus
Related Areas of Cardiovascular Research Interest
Role of leptin and malonyl CoA in obesity
Summary of Cardiovascular Research Interest
Diabetes mellitus has been associated with the deterioration of microvasculature in the brain, eye, and kidney, the insulin insensitive tissues. In the brain diabetes disrupts blood-brain barrier and leads to cognitive decline. In the eye, it leads to retinopathy and in the kidney to end-stage renal disease.
The main focus of our research is to slow down the effect of diabetes-induced mitochondrial oxidative stress on the microvasculature of the brain, eye and the kidney, by inhibition of mitochondrial carbonic anhydrases (mCA). We use mCA double knockout mice, pharmacological inhibitors of mCA, conditionally immortal cell lines (brain and retinal pericytes and kidney podocytes), and our expertise in the areas of cell biology, molecular biology and biochemistry to achieve our goals.
We have shown, in diabetic-mice, decreased reduced glutathione (GSH) and increased superoxide dismutase (SOD), 4-hydroxy-2-trans-nonenal (HNE) and 3-nitrotyrosine (3-NT), indicating oxidative stress and its reversal by topiramate, a well known inhibitor of mCA. The genetic knockout of mCA resulted in less oxidative stess even in non-diabetic mice compared to littermate controls providing evidence for a role of mCA in oxidative metabolism of glucose and production of reactive oxygen species and oxidative steress.
Our most interesting finding is the rescue of cerebral pericyte (PC) dropout in diabetic mice, by topiramate treatment. Although the microvacualture of the brain is made up of specialized endothelial cells (EC), PC in immediate contact and are vital for the integratity of the microvessels. Further studies are in progress to show a correlation between PC drop out, blood-brain barrier disruption and cognitive decline in diabetes and its reversal by mCA inhibition.
Similar studies are also in progress in the eye and the kidney.
We are also interested in determining the role of leptin and malonyl CoA in obesity. We have identified ATP synthase α as a leptin binding protein in the isolated brain microvessels by afinity chromatography and MS/MS. As for malonyl CoA, our preliminary studies provide evidence that NO may be involved in AMPK/ACC/malonyl CoA pathway in the mouse hypothalamus.