; Proteoglycans are the most complex glycoconjugates that play pivotal roles in vasculature. They consist of a protein moiety with two or more glycosaminoglycan (GAG) side chains such as heparan sulfate (HS), chondroitin sulfate (CS), dermatan sulfate (DS) and keratan sulfate (KS). HS is the most widely studied among all GAGs. The fine structures of HS, in terms of their sulfation pattern, epimerization and domain organization, dramatically affect their ability to bind to a wide variety of proteins, including growth factors, proteases, protease inhibitors, adhesive proteins, chemokines and cytokines, which in turn are shown to regulate various vascular pathophysiological processes such as hemostasis, thrombosis, hypoxia, sepsis, inflammation and angiogenesis. GAG-protein, GAG-cell and GAG-ECM interactions are shown to be dysregulated during these vascular pathological conditions exacerbating the disease conditions. These dysregulated interactions are attributed to both increased or decreased expression of proteoglycans and their remodeling enzymes such as extracellular sulfatases as well their increased shedding from endothelial cells. Our knowledge of HS fine structures that regulate these interactions and factors that regulate HS biosynthesis during the disease progression will advance our ability to harness the therapeutic potential of HS in combating vascular diseases. In addition, understanding the importance of GAG multivalency will guide us in fine tuning the cellular processes to ameliorate vascular disorders. In this application, we propose to (a) use enzymatic strategy, originally developed by the PI, to assemble a panel of HS structures to determine the structural parameters that are essential for interactions with coagulation proteases and cytokines/chemokines, (b) to harness the therapeutic potential of GAGs through stimulating the biosynthesis of proteoglycan mimetics using synthetic scaffolds and (c) to modulate HS biosynthesis to better define the role of HS sulfation pattern in angiogenesis.
Vascular injuries are among the most debilitating and leading causes of deaths in USA. Furthermore, they represent number one in the total national health care cost. Currently there are a limited number of drugs available of which heparin is most widely used as anticoagulant though it has numerous side effects. This proposal aims to understand the biological role of heparin like molecules at the molecular level and the factors that regulate their biosynthesis with the final goal of developing cardiovascular drugs.
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