Metabolic interactions in the vascular wall: an integrated experimental and computational approach

项目总结

Project Summary Nearly 1 in 3 American adults has metabolic syndrome, a complex disorder defined by elevations in blood sugar, cholesterol, and triglycerides. Patients with metabolic syndrome have a high cardiovascular disease risk due to interactions among the elevated blood metabolites. However, since we do not have good methods for studying integrated and interacting metabolic changes, we treat each metabolic abnormality individually. As a result, patients are often on multiple medications, potentially decreasing the ability of each drug to normalize blood metabolites and raising the risk for negative drug interactions. In this project, we propose a novel integrated experimental and computational bioengineering approach to study how metabolic abnormalities contribute to cardiovascular disease. Specifically, we will study metabolic interactions between endothelial cells, which line the inside of the blood vessels, and vascular smooth muscle cells, which contribute to cardiovascular disease when they change their function. We will engineer a computational isotope-assisted metabolic flux analysis (iMFA) model, which uses experimental mass spectrometry data to estimate intracellular metabolic fluxes and metabolite transport. The computational model will enable us to develop new hypotheses for and plan studies into how metabolic changes (from altered blood metabolites or therapies) affect the vascular wall. We hypothesize that EC metabolic dysfunction increases the transport of metabolites that promote VSMC to switch from a contractile to a synthetic phenotype. In turn, synthetic vSMC enhance EC metabolite transport to support proliferation. To explore this hypothesis, we will combine in vitro, in silico, and ex vivo studies to: 1) Determine how EC dysfunction in altered metabolic environments impacts metabolite transport; 2) Measure how altered metabolites synergistically shift vSMC to a synthetic phenotype; and 3) Investigate how EC-vSMC crosstalk impacts cell metabolism and phenotype in the vascular wall. We will start with single cell models of endothelial and vascular smooth muscle cells, which will simulate the diversity of human nutrient levels. We will the integrate the two cell types to understand their crosstalk in vitro, in silico, and ex vivo. At each step, we will relate metabolism to cell phenotype and function to link the model to cardiovascular disease. The computational iMFA model of integrated endothelial-vascular smooth muscle cell metabolism, transport, and function will enable us to develop new hypotheses for and plan studies into how metabolic changes from altered blood metabolites or therapies affect the vascular wall. By changing the parenchymal cell type, the model can then be extended to study vascular metabolic interactions in other tissues (e.g., brain) and shed light into other diseases in which integrated EC metabolism and transport (e.g., Alzheimer’s disease).