Defining Vascular Functions of Proteoglycans through Chemical Biology Approaches

通过化学生物学方法定义蛋白多糖的血管功能

• 批准号: 8516574
• 负责人: KUBERAN BALAGURUNATHAN
• 金额: $ 81.56万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8516574
• 关键词: Address; Adhesives; Adverse effects; Affect; Anabolism; Animal Model; Anticoagulants; Binding; Biochemical; Biological; Biology; Blood Coagulation Disorders; Blood Vessels; Cardiovascular Agents; Cause of Death; Cell Transplants; Cell physiology; Cells; Chemicals; Chemistry; Coagulation Process; Complex; Dermatan Sulfate; Development; Disabled Persons; Disease; Disease Progression; Endothelial Cells; Enzymes; Escherichia coli; Event; Extracellular Matrix; Foundations; Glycoconjugates; Glycosaminoglycans; Glypican; Goals; Graft Rejection; Growth Factor; Health Care Costs; Hemostatic function; Heparan Sulfate Biosynthesis; Heparan Sulfate Proteoglycan; Heparin; Heparitin Sulfate; Heparitin sulfotransferase; Housing; Hypoxia; IL8 gene; In Vitro; Inflammation; Inflammatory; Injury; Instruction; Keratan Sulfate; Knowledge; Laboratories; Libraries; Ligands; Link; Methodology; Modification; Molecular; Nature; Organ; Pattern; Peptide Hydrolases; Pharmaceutical Preparations; Physiological; Physiological Processes; Play; Polysaccharides; Process; Protease Inhibitor; Protein Isoforms; Proteins; Proteoglycan; Recombinants; Regulation; Research; Research Personnel; Role; Sepsis; Side; Structure; Structure-Activity Relationship; Sulfatases; System; Technology; Testing; Therapeutic; Thrombosis; Transplantation; Universities; Utah; Vascular Diseases; Vascular System; Work; Xeno; angiogenesis; base; capsular polysaccharide K5; chemokine; combat; cytokine; dermatan sulfate chondroitin sulfate; design; epimerization; experience; extracellular; handicapping condition; in vivo; inhibitor/antagonist; mimetics; new technology; novel; programs; receptor; scaffold; small molecule; sulfation; sulfotransferase; syndecan

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.

项目负责人（最后，第一，中间）：库伯兰的Balagurunathan SUI \/lli/iary项目（请参阅说明）； 蛋白聚糖是在脉管系统中起关键作用的最复杂的糖缀合物。它们由 蛋白质部分具有两个或多个糖胺聚糖（GAG）的侧链，例如硫酸乙酰肝素（HS）， 硫酸软骨素（CS），硫酸皮肤菌（DS）和硫酸角盐（KS）。 HS是研究最广泛的 在所有插科打.。 HS的精细结构，就其硫酸化模式，表达和结构域而言 组织，极大地影响了它们与各种蛋白质结合的能力，包括生长因素， 蛋白酶，蛋白酶抑制剂，粘合蛋白，趋化因子和细胞因子，而这些因子又显示为 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，插科打蛋白和GAG-ECM相互作用被证明是 在这些血管病理状况下，失调加剧了疾病。这些 失调的相互作用归因于蛋白聚糖的表达增加或降低 它们的重塑酶，例如细胞外硫酸酶以及内皮的脱落的增加 细胞。我们对HS细胞结构的了解，这些结构调节了这些相互作用和调节HS的因素 疾病进展过程中的生物合成将提高我们利用治疗潜力的能力 HS对抗血管疾病。此外，了解堵嘴多价的重要性将 指导我们微调细胞过程以改善血管疾病。在此应用程序中，我们 建议（a）使用最初由PI开发的酶促策略组装HS结构的面板 确定对于与凝血蛋白酶相互作用至关重要的结构参数 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 使用合成支架和（c）调节HS生物合成以更好地定义蛋白聚糖的模拟物 HS硫酸化模式在血管生成中的作用。 相关性（请参阅说明）： 血管损伤是美国最令人衰弱和主要的死亡原因之一。此外，他们 代表国民保健总成本中的第一名。目前的药物数量有限 可用的肝素最广泛用作抗凝剂，尽管它具有许多副作用。这 建议旨在了解分子水平和分子的肝素之类的生物学作用 通过开发心血管药物的最终目标来调节其生物合成的因素。