An important long-term goal in the approach to treating atherosclerosis and hypertension is to understand the mechanisms which regulate the structure of blood vessels; a process we will term """"""""vascular remodeling."""""""" Our goal is to identify genes that mediate vascular remodeling in response to changes in blood flow in the carotid. An important predictive phenotype for human cardiovascular disease is remodeling in the carotid represented by the measurement termed intima-media thickening (IMT). Measuring the IMT has been proposed as a method to detect early atherosclerosis and may predict the subsequent risk of stroke, myocardial infarction, and peripheral vascular disease. The proposed project takes advantage of our well characterized flow model that stimulates remodeling in the mouse carotid in a very reproducible manner. Preliminary data show a 25-fold difference in vascular remodeling in SJL/J compared to C3H/HeJ mice (measured by growth of the intima relative to the media, a phenotype we term I/M). Our major hypothesis is that a small number of genes are critical for the I/M phenotype difference in SJL/J and C3H/HeJ mice. Based on these data our major goal is to perform a C3H/HeJ x SJL/J/cross and total genomic scan to identify the genes that contribute to the I/M phenotype. To prove this hypothesis four aims are proposed.
Aim 1 : Intercross C3H/HeJ and SJL/J to obtain 200 F2 progeny that express a range of remodeling phenotypes.
Aim 2 : Genotype P0, F1 and F2 mice and use interval mapping to determine the chromosomal location of the quantitative trait loci (QTL) that are responsible for flow-induced remodeling based on the I/M phenotype.
Aim 3 : Create congenic strains of C3H/HeJ mice that express SJL/J genes associated with high I/M phenotypes.
Aim 4 : Perform microarray analysis on the carotids of congenic strains to characterize mRNAs uniquely expressed and thereby identify physiologic mechanisms. This proposal represents the first step in elucidating the genetics of vascular remodeling which may yield new therapeutic approaches to diseases such as carotid and coronary atherosclerosis. ? ?
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