Vascular calcification is more common in patients with diabetes compared to the general population and is associated with increased mortality, stroke, and amputations. Furthermore, bone formation and mineralization are impaired in diabetes. Recent studies have demonstrated that vascular calcification is an active and tightly regulated process that resembles mineralization in bone suggesting a link between these two processes. Our preliminary data demonstrate the presence of the osteoblast differentiation factor, core binding factor alpha subunit 1 (Cbfa1), and increased expression of bone matrix proteins osteopontin and type I collagen (downstream products of Cbfa1) in calcified arteries in diabetic dialysis patients compared to non-diabetic patients. Our preliminary data also demonstrate glucose upregulates Cbfa1 in bovine vascular smooth muscle cells (BVSMC) and downregulates Cbfa1 in osteoblasts (OB). Therefore, I plan to test the hypothesis that glucose-induced upregulation of the osteoblast transcription factor Cbfa1 in vascular smooth muscle cells (VSMC) and downregulation of Cbfa1 in osteoblasts (OB) is responsible for the increased vascular calcification and impaired bone formation in patients with diabetes.
Specific Aim1 is designed to demonstrate that elevated glucose enhances calcification and increases the expression of Cbfa1 and bone matrix proteins, osteopontin, osteocalcin, and alkaline phosphatase in BVSMC and demonstrate the opposite effect in osteoblasts. I will also determine the cell signaling pathways by which this process occurs in Specific Aim 2.
In Specific Aim 3, I will confirm the clinical relevance of our work by evaluating the effect of serum from patients with different levels of glycemic control using in vitro models. Determining the mechanisms by which vascular calcification occurs may provide insight into the pathogenesis of the accelerated vascular disease observed in patients with diabetes. The techniques learned and collaborations developed outside of my present field in this K01 proposal will allow me to extend my work evaluating vascular calcification in dialysis patients to diabetic patients, leading to a research focus that will enable me to become an independent investigator.
| Moe, Sharon M; Chen, Neal X (2008) Mechanisms of vascular calcification in chronic kidney disease. J Am Soc Nephrol 19:213-6 |
