An important long-term goal in treating atherosclerosis and hypertension is to understand the mechanisms that 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. An important predictive phenotype for human cardiovascular disease is remodeling in the carotid artery represented by the measurement termed intima-media thickening (IMT). In this renewal of HL62826 we propose to gain insight into the mechanisms responsible for vascular remodeling by combined genetic and physiologic approaches that involves congenic mouse strains which differ in remodeling phenotypes. In the previous grant periods we developed and published a reproducible and quantitative model for flow-dependent vascular remodeling. Using this model to study inbred mice we have identified a clinically relevant trait - the carotid intima in the presence of decreased flow that differs by >25-fold between the SJL/J (referred to as SJL) and C3HeB/FeJ (referred to as C3H/F) strains. We performed a QTL analysis of remodeling alleles in a backcross of these strains and identified two major QTLs: termed the Intima modifier loci (lm1 on chromosome 2 and lm2 on chromosome 11). Our major hypothesis is that genes in two Intima modifier loci (Im1 and Im2) are key contributors to intima formation. Based on our preliminary data our goal is to employ an integrative genomic approach to identify candidate genes that control the Im1 and Im2 loci. Using a combination of analyses including congenic mapping, transcriptional analysis, and pathway analysis we will reduce the number of genes to ~ 200. Based on pathophysiologic criteria we will then perform cell specific functional analyses on ~20 candidate genes, and use the results to identify 3 to 5 intima candidate genes that we will study in transgenic mouse models. We propose the following Aims.
Aim 1 : Identify candidate genes within Im1 and Im2 loci using congenic strains. Hypothesis: Small regions on mouse chromosomes 2 and 11 will explain variation of the intima trait.
Aim 2 : Characterize functions of Intima candidate genes in smooth muscle and endothelial cells. Hypothesis: The vessel wall is a primary mediator of intima formation.
Aim 3 : Evaluate candidate genes present in bone-marrow cells that contribute to the intima trait. Hypothesis: Circulating leukocytes contribute to intima formation associated with the Im2 locus. The project takes advantage of our well-characterized flow model, the dramatic remodeling phenotype, and expertise in genetics, transcriptomics and physiological techniques. Characterizing Im1 and Im2 is the first step to understand the genetic basis for human IMT and to develop new approaches to treat atherosclerosis.
The failure of drugs and devices such as stents for treatment of vascular disease has been disappointing. Thus our genetic approach to identify novel genes in the vasculature that regulate remodeling should open several new lines of investigation. Elucidating the tissue- and cell-specific pathways by which vessels remodel in response to low flow should provide insights for therapies to improve vascular function in atherosclerosis, hypertension, and stroke.
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