Dedifferentiation and proliferation of vascular smooth muscle ceils (vSMC) is critical to the onset and progression of environmentally induced atherosclerosis. Studies are proposed to simplify the study of global mRNA expression and cellular behavior of vSMCs at any given time or phenotypic state using a multiple binary expression system. Using the rules of Boolean genetic networks, we will identify specific genes expressed as vSMCs transition from one phenotype to another, as well as the transcriptional contextual network in which these changes occur.
The specific aims of this project are to: 1) Map the transcriptome of five distinct vSMC phenotypes: Quiescence, differentiation, proliferation, migration, and apoptosis. The specified vSMC phenotypes will constitute endpoints of the gene expression landscape at any given point in time. By varying the phenotypic start point, movement across the phenotypic spectrum will be mapped using Affymetrix gene chips; 2) Formulate contextual, predictive clusters of genes that mediate movement across cell behaviors. The Boolean network methodology provides a framework to describe contextual gene expression, as well as progression from one phenotypic state or """"""""attractor"""""""" to the next. With these analyses in hand, prediction of changes in cell behavior as determined by individual mRNA fingerprints will be made; 3) Define interactive networks predictive of environmentally-induced atherogenesis. With a model of vSMC in vitro behavior in hand, the next step will be to validate its usefulness in vivo. Mice feed an atherogenic diet will be challenged with benzo(a)pyrene to modulate overlapping signal transduction cascades leading to atherogenic vSMC phenotypes. The gone clusters altered by oxidant stress will be identified to gain insight into the biological basis of environmentally induced atherosclerotic vascular disease.
| Johnson, Charles D; Balagurunathan, Yoganand; Tadesse, Mahlet G et al. (2004) Unraveling gene-gene interactions regulated by ligands of the aryl hydrocarbon receptor. Environ Health Perspect 112:403-12 |
