Defining Vascular Functions of Proteoglycans through Chemical Biology Approaches

项目负责人（最后，第一，中间）：Balagurunathan，Kuberan 项目SUI\/lli/IARY（参见说明）; 蛋白聚糖是最复杂的糖复合物，在血管系统中起着关键作用。它们由一个 具有两个或多个糖胺聚糖（GAG）侧链的蛋白质部分，如硫酸乙酰肝素（HS）， 硫酸软骨素（CS）、硫酸皮肤素（DS）和硫酸角质素（KS）。HS是研究最广泛的 在所有的GAGs中。HS的精细结构，根据其硫酸化模式，差向异构化和结构域， 组织，极大地影响它们与各种蛋白质结合的能力，包括生长因子， 蛋白酶、蛋白酶抑制剂、粘附蛋白、趋化因子和细胞因子，它们又显示出 调节各种血管病理生理过程，例如止血、血栓形成、缺氧、败血症， 炎症和血管生成。GAG-蛋白质、GAG-细胞和GAG-ECM相互作用显示为 在这些血管病理状况期间失调，加重了疾病状况。这些 失调的相互作用归因于蛋白聚糖表达的增加或减少， 它们的重塑酶如细胞外硫酸酯酶以及它们增加的从内皮细胞的脱落 细胞我们对调节这些相互作用的HS精细结构和调节HS的因子的了解 在疾病进展过程中的生物合成将提高我们利用生物合成的治疗潜力的能力。 HS治疗血管疾病。此外，了解GAG多价性的重要性， 指导我们微调细胞过程以改善血管疾病。在本申请中，我们 我建议（a）使用最初由PI开发的酶促策略来组装一组HS结构 确定与凝血蛋白酶相互作用所必需的结构参数， 细胞因子/趋化因子，（B）通过刺激生物合成来利用GAG的治疗潜力 和（c）调节HS生物合成以更好地定义蛋白聚糖模拟物， HS硫酸化模式在血管生成中的作用。 相关性（参见说明）： 在美国，血管损伤是导致死亡的最主要原因之一。而且他们 在全国医疗保健总成本中排名第一。目前，药物数量有限， 其中肝素最广泛地用作抗凝剂，尽管它具有许多副作用。这 该提案旨在了解肝素样分子在分子水平上的生物学作用， 调节其生物合成的因子，最终目标是开发心血管药物。

Project Leader (Last, First, Middle): Balagurunathan, Kuberan PROJECT SUI\/lli/IARY (See instructions); 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. RELEVANCE (See instructions): 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.