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

基本信息

批准号：
9068300
负责人：
KUBERAN BALAGURUNATHAN
金额：
$ 67.05万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
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/9068300
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 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 PPBP gene 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 Universities Utah Vascular Diseases Vascular System Work Xenograft procedure angiogenesis base 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 inhibitor sulfation sulfotransferase syndecan

项目摘要

PROJECT SUMMARY (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.

项目摘要（参见说明）；蛋白聚糖是最复杂的糖复合物，在脉管系统中发挥着关键作用。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，例如硫酸乙酰肝素（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 GAG 中。 HS 的精细结构，包括硫酸化模式、差向异构化和结构域组织，极大地影响它们与多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，这些又被证明调节多种血管病理生理过程，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 相互作用被证明是在这些血管病理状况期间失调，加剧了疾病状况。这些失调的相互作用归因于蛋白聚糖表达的增加或减少以及它们的重塑酶（例如细胞外硫酸酯酶）以及内皮细胞脱落的增加细胞。我们对调节这些相互作用的 HS 精细结构以及调节 HS 的因素的了解疾病进展期间的生物合成将提高我们利用其治疗潜力的能力 HS对抗血管疾病。此外，了解 GAG 多价的重要性将有助于指导我们微调细胞过程以改善血管疾病。在这个应用程序中，我们建议 (a) 使用最初由 PI 开发的酶策略来组装 HS 结构面板确定与凝固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 的治疗潜力使用合成支架的蛋白多糖模拟物和（c）调节HS生物合成以更好地定义 HS 硫酸化模式在血管生成中的作用。相关性（参见说明）：血管损伤是美国最令人衰弱和死亡的主要原因之一。此外，他们在全国医疗保健总费用中排名第一。目前药品数量有限其中肝素是最广泛使用的抗凝剂，尽管它有许多副作用。这该提案旨在从分子水平上了解类肝素分子的生物学作用以及调节其生物合成的因素，最终目标是开发心血管药物。