The goals of this project are twofold: First we will identify candidate genes related to insulin resistance and hypertension using the fructose- fed rat model. We will employ differential mRNA display to identify and isolate genes which exhibit changes in expression as these animals become insulin resistant and hypertensive. Detailed molecular characterization of individual candidate genes will be based on : l) those whose expression is 'normalized' by administration of troglitazone, a drug which prevents the development of insulin resistance and hypertension in fructose-fed rats; or 2) those which correspond to previously identified genes or are novel but contain functional motifs which logically implicate their role in insulin responsiveness and blood pressure regulation. This data will provide 1) relevant information regarding the interrelationship of physiologic mechanisms of insulin action and blood regulation and 2) candidate genes for linkage analysis in our MA population. When particularly interesting genes are identified, either through differential display or through the linkage analysis or both. we will utilize transgenic mice to determine a mechanistic role for candidate genes in the pathogenesis of insulin resistance and hypertension. The second goal will be to pursue our finding that variations in blood pressure in man are linked to the lipoprotein lipase (LPL) loci. We will correlate blood pressure levels and tissue LPL mRNA expression in mice transgenic for the human LPL gene, heterozygote mice with the LPL knockout, and mice with tissue specific replacement of LPL with a null background. Since LPL activity is low in insulin resistant models, hypertensive modes, we predict lower blood pressure will be associated with higher LPL levels.
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