This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetes is a leading risk factor for cardiovascular morbidity and mortality, and is associated with accelerated large-vessel atherosclerosis as well as microvascular retinopathy and nephropathy. The direct effects on the endothelium include hyperglycemia and insulin signal dysregulation;indirect effects include altered substrate metabolism and protein glycation. We have developed methods for the rapid isolation of endothelial cells after in vivo exposure to hyperglycemia. We will use these methods to evaluate gene regulation in vascular endothelial cells and thereby identify transcriptional responses to hyperglycemia. We consider that these responses will allow elucidation of biochemical damage that precipitates the vascular complications of diabetes. Our application is further driven by the hypothesis that our in-depth transcriptional analysis will distinguish the molecular effects of insulin regulation from the metabolic effects of hyperglycemia. We will take advantage of two murine models to investigate endothelial gene regulation: 1. streptozotocin treatment as a model of insulin deficiency and type I diabetes, and 2. chronic dietary exposure to high-fat plus sucrose as model of hyperinsulinemia and type II diabetes.
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