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DDDAS Design of Drug Interventions for the Treatment of Dyslipidemia in ApoE-/- Mice

Brittney Metts, Sean Thatcher, Eboni Lewis, Mike Karounos, Lisa Cassis, Rebecca Smith and Robert A Lodder

Computational models of complex systems, such as signaling networks and biological systems, can be used to explain the behavior of such systems under various conditions. The large number of integrated processes and variables, and the nonlinearities inherent in the fundamental processes, make it difficult for scientists unassisted by computer simulations to effectively predict the consequences of a particular intervention. For this reason, computer simulation has become an important tool for generating hypotheses about the behavior of these systems that can then be tested in the laboratory and clinic. A dynamic data-driven application simulation (DDDAS) was designed by Biospherics to model complex metabolic disease pathways by testing potential binary therapies in simulations at various combinations of two points in the pathways. Since DDDAS chooses the most effective pair-wise combinations, this data-driven system allows for the implementation of real-time data to model or predict a measurement or event. By incorporating data dynamically rather than statically, the predictions and measurements become more reliable. Dyslipidemia, a common precursor to atherosclerosis, can be manifested by high triglycerides, increased apolipoprotein (Apo) B, high levels of LDL, and low levels of HDL. SPX106 and D-tagatose is a combination drug therapy composed of a carbohydrate, D-tagatose, and SPX106. D-tagatose has been studied for the treatment of diabetes for several years, and has the ability to lower blood insulin levels and to decrease glycogen formation. SPX106 is a natural substance that accelerates lipid catabolism and inhibits dyslipidemia. In apolipoprotein E knockout mice (ApoE-/-), this drug combination has been shown to significantly lower both the amount of atherosclerosis and blood cholesterol levels. This study used 26 male ApoE-/- mice- (n=13 in each group, control and treated). The control group received the normal “Western” diet (Harlan TD88137) and the treatment group received a modified version in which the sucrose was replaced with D-tagatose and 1g of SPX106 was added for every kilogram of chow. Mice were fed the diet for 8 weeks and then sacrificed via cardiac puncture. Blood serum was analyzed for cholesterol concentration. A significant difference was observed between the control and treated groups for total cholesterol levels. FPLC separations were done on fractions from both control and treated groups. A significant difference between VLDL and HDL levels was found between the treated and control mice (p<0.05 for both). Aortas were also taken and preserved in formalin to be quantified for atherosclerosis. Aortic sinuses were frozen in OCT and sectioned using a cryostat and then quantified for atherosclerosis. Treated mice showed statistically significant reduction in atherosclerosis in the aortic arch (p<0.01), the thoracic aorta (p<0.05), and the aortic sinus (p<0.05) as well as a reduction of cholesterol (p<0.05).