This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this proposal is to investigate the role of chondroitin sulfate (CS) and dermatan sulfate (DS) proteoglycan biosynthesis in atherogenesis. As an atherosclerotic lesion develops in the blood vessel wall, CS and DS proteoglycans biglycan, decorin, and versican accumulate. Because lipoproteins bind in vitro to proteoglycans and co-localize with them in the atherosclerotic lesion, it has been hypothesized that increased proteoglycan biosynthesis by cells in the vessel wall is atherogenic. Biglycan is a likely candidate proteoglycan for binding and retaining lipoproteins since it binds atherogenic lipoproteins in vitro, colocalizes with apolipoprotein B (apoB) and E (apoE) in human atherosclerotic lesions, and more closely colocalizes with apoB and apoE in mouse lesions than decorin. Furthermore, because biglycan has both protein and glycosaminoglycan (GAG)-mediated interactions with other proteins (e.g. collagens, lipoproteins, TGFbeta), we hypothesize that these interactions are important to the structure and development of the lesion in the vascular wall. To test these hypotheses our three aims focus on measuring and characterizing atherosclerosis in 3 animal models, In specific aim 1, we will determine whether increased biosynthesis of biglycan by endothelial cells can exaggerate the development of atherosclerosis.
In specific aim 2, we will determine whether increased biosynthesis of biglycan by vascular smooth muscle cells can exaggerate the development of atherosclerosis.
In specific aim 3, we will determine whether the GAG modifications of biglycan are important for atherosclerotic lesion development and structure. All three mouse models will be made atherogenic by crossing them to either low-density lipoprotein receptor deficient or apolipoprotein E deficient mice. Our objectives with these mouse models of atherosclerosis are to determine the roles increased biosynthesis and GAG modification of biglycan have in atherosclerotic lesion development and progression. In addition to standard atherosclerotic lesion analysis and extensive histologic characterization including immunohistochemistry for different collagen types and biglycan, intravital microscopy and magnetic resonance imaging will be used to characterize the vascular pathology in these mice. Overall, these proposed studies will more clearly define the role biglycan accumulation and biglycan GAG modification have in the pathogenesis of atherosclerosis.
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