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Molecular basis of atherosclerosis induced by hypercholesterolemia and type 2 diabetes

Obiettivo

Atherosclerosis and associated cardiovascular disease (CVD) is facilitated by several genetic and environmental risk factors, including hyper-cholesterolemia, diabetes, hypertension and smoking. Human diabetes is a multi-system disorder that results from progressive failure of insulin secretion and insulin resistance. Streptozotocin (STZ) has been widely used as a model to induce type 1 diabetes (insulin-dependent) as a result of its citotoxic activity in pancreatic b-cells. STZ treatment accelerates atherosclerosis in a wide spectrum of experimental animals, thus providing an appropriate model to identify molecular mechanisms involved in increased risk of CVD induced by type 1 diabetes. However, 90% of diabetic patients with premature CVD suffer from type 2 diabetes (non-insulin dependent) and the molecular mechanisms underlying this predisposition are largely unknown mainly because the lack of suitable experimental models.

In the present project, we will pursue two main objectives:
a) Generation and characterization of an animal model of atherosclerosis accelerated by type 2 diabetes. To this end, we will generate mice double deficient in apolipoprotein E and Insulin Receptor Substrate-2 (apoE-IRS-2-KO) and compare the kinetics of atherosclerosis versus mice single deficient in apoE (apoE-KO). Previous studies have shown that apoE-KO mice develop spontaneous atherosclerosis, and IRS-2-KO mice develop type 2 diabetes and display accelerated development of vascular obstructive lesions induced by mechanical injury to the arterial wall;
b) Identify changes in gene expression associated to atherosclerosis induced by hyper-cholesterolemia and diabetes.

To this end, we will compare DNA micro-array analysis from aortic tissue from apoE-KO and apoE-IRS-2-KO mice fed low-fat standard diet. These studies should improve our knowledge of the molecular mechanisms underlying atherosclerosis induced by hyper-cholesterolemia and type 2 diabetes, two main risk factors of CVD.

Campo scientifico (EuroSciVoc)

Parole chiave

Argomento(i)

Invito a presentare proposte

FP6-2004-MOBILITY-5
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Meccanismo di finanziamento

EIF - Marie Curie actions-Intra-European Fellowships

Coordinatore

CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
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