Fucosyl transferases in inflammation and angiogenesis

岩藻糖基转移酶在炎症和血管生成中的作用

• 批准号: 8195409
• 负责人: ALISA E KOCH
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195409
• 关键词: Adhesions; Affect; Antigens; Arthritis; Autoimmune Diseases; Binding; Biological Process; Blood Vessels; Cell Adhesion; Cell Adhesion Molecules; Cell surface; Cells; Chemotaxis; Chronic; Contact Dermatitis; Data; Defect; Development; Disease; E-Selectin; Endothelial Cells; Enzymes; Family; Fibroblasts; Fucosyltransferase; Future; Gelatinase A; Genes; Glycoconjugates; Growth; Human; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Intercellular adhesion molecule 1; Joints; Leukocytes; Ligands; Light; Lymphoid; Malignant Neoplasms; Mediating; Mediator of activation protein; Mission; Modeling; Monoclonal Antibodies; Mus; Myelogenous; Nature; Organ; Pathogenesis; Population; Process; Production; Psoriasis; Resistance; Rheumatoid Arthritis; Rhus radicans; Role; Selectins; Skin; Solid Neoplasm; Synovial Membrane; Therapeutic; Thymus Gland; Tissues; Transferase; Veterans; Wound Healing; abstracting; angiogenesis; arthritis therapy; base; cytokine; glucose analog; in vivo; joint destruction; monocyte; novel; public health relevance; selective expression; therapy development; tumor growth

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Rheumatoid arthritis (RA) is characterized by exuberant angiogenesis and leukocyte infiltration in the synovial tissue (ST). We have shown that the soluble adhesion molecule E-selectin (sE-selectin) induces angiogenesis in RA (see Koch et. al, Nature 376:517). The mechanism by which this molecule mediates angiogenesis is by binding sialyl Lewisx on endothelial cells (ECs). It is likely that cytokines present in the inflammatory milieu upregulate the production of cell surface adhesion molecules. These molecules are then shed and induce other endothelial cells to begin the angiogenic process. We have developed a novel monoclonal antibody (mAb) 4A11 by immunizing mice with cells from inflamed human ST lining joints. This mAb detects an antigen expressed on ECs in synovium, skin, thymus, and lymphoid organs. Moreover, this antigen is inducible and upregulated in human RA ST. MAb 4A11 detects the glycoconjugates H-5-2 (abbreviated H) and Lewisy-6 (Ley), collectively termed Ley/H. Additionally, Ley is structurally very similar to Lex, whose sialylated form is the EC ligand for the angiogenic mediator sE- selectin. We have found that these glycoconjugates, or easily obtainable glucose analogs of these glycoconjugates, termed H-2g and Leyg, respectively, are angiogenic in vivo, mediate monocyte recruitment and leukocyte-EC adhesion, as well as induce RA ST fibroblast production of matrix metalloproteinase-2. Synthesis of Ley and H are controlled by fucosyl transferases (termed futs). Our preliminary data suggests that fut1 deficient mice are also deficient in development of both angiogenesis and arthritis. The aim of the proposed studies is to examine the role of futs in inflammation and angiogenesis. We will determine: I) if fut1 gene deficient mouse microvascular ECs display alterations in leukocyte adhesion and angiogenesis in vitro; II) fut1 gene deficient mice display defective leukocyte recruitment in vivo; III) mice display defective angiogenesis in vivo; and if IV) fut1 gene deficient mice are resistant to arthritis development in vivo. The proposed studies are very relevant to the VA mission, as arthritidies, such as RA, are very common conditions affecting a large proportion of the population each year. Our results would additionally have potential therapeutic benefits to conditions characterized by leukocyte recruitment and angiogenesis, such as wound repair and solid tumor growth. Ever rising numbers of veterans each year are afflicted by malignancies and our results may eventually benefit these veterans too. Thus, the proposed studies should initially shed light on futs as likely novel targets in RA therapy. Examining fut1 deficient mice, in which synthesis of Ley/H is impaired, provides a rare opportunity to establish a role for fucosylation in inflammation, arthritis and angiogenesis. These studies should form the basis for us to investigate the role of futs in human RA in the future as well as potentially open up an entirely new family of targets for the treatment of RA. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Rheumatoid arthritis (RA) is an autoimmune disease affecting 1% of the population. Inflammation, cell recruitment, and angiogenesis are all vital components of the pathogenesis of RA. We have found that enzymes termed fucosyl transferases are important to these processes in inflammatory arthritis. As Veteran's suffer from a number of disorders in which angiogenesis is important, such as wound repair and tumor growth, these studies may have broad applicability to developing therapies for angiogenesis dependent diseases. Additionally, initially, studies such as these may open up a new family of targets in RA therapy.

描述(由申请人提供)： 项目摘要/摘要类风湿性关节炎(RA)的特点是滑膜组织(ST)血管生成旺盛，白细胞浸润。我们已经证明，可溶性黏附分子E-选择素(SE-选择素)可诱导RA血管生成(见Koch et。Al，自然376：517)。该分子介导血管生成的机制是通过结合内皮细胞(ECs)上的唾液酸路易斯X。炎症环境中存在的细胞因子可能上调细胞表面黏附分子的产生。然后，这些分子被释放，并诱导其他内皮细胞开始血管生成过程。我们用发炎的人ST衬里关节细胞免疫小鼠，研制出一种新型的单抗(MAb)4A11。该单抗检测滑膜、皮肤、胸腺和淋巴器官中ECs上表达的抗原。此外，该抗原在人RA ST中是可诱导和上调的。MAB 4A11检测到糖结合物H-5-2(缩写H)和Lewis-6(LEY)，统称为LEY/H。此外，LEY在结构上与Lex非常相似，Lex的唾液酸化形式是血管生成介质sE-选择素的EC配体。我们发现，这些糖结合物或这些糖结合物的葡萄糖类似物，分别命名为H-2G和Leyg，在体内是血管生成的，介导单核细胞募集和白细胞-EC黏附，并诱导RA ST成纤维细胞产生基质金属蛋白酶-2。Ley和H的合成受岩藻糖基转移酶(FUTS)的控制。我们的初步数据表明，FUT1缺陷小鼠在血管生成和关节炎的发育方面也存在缺陷。这项拟议研究的目的是研究FUTS在炎症和血管生成中的作用。我们将确定：i)FUT1基因缺陷的小鼠微血管内皮细胞在体外是否表现出白细胞黏附和血管生成的变化；ii)FUT1基因缺陷的小鼠在体内表现出缺陷的白细胞募集；III)小鼠在体内显示出缺陷的血管生成；以及IV)FUT1基因缺陷的小鼠是否在体内抵抗关节炎的发展。拟议的研究与退伍军人事务部的任务非常相关，因为关节炎，如类风湿性关节炎，是每年影响很大比例人口的非常常见的疾病。我们的结果还将对以白细胞募集和血管生成为特征的疾病具有潜在的治疗益处，例如伤口修复和实体瘤生长。每年都有越来越多的退伍军人受到恶性肿瘤的困扰，我们的结果最终可能也会让这些退伍军人受益。因此，拟议的研究应该初步阐明FUTS可能是RA治疗的新靶点。研究FUT1缺陷小鼠的Ley/H合成受损，为确定岩藻糖化在炎症、关节炎和血管生成中的作用提供了难得的机会。这些研究将为我们未来研究FUTS在人类类风湿关节炎中的作用奠定基础，并有可能为类风湿关节炎的治疗开辟一个全新的靶点家族。 公共卫生相关性： 项目简介类风湿性关节炎(RA)是一种影响1%人口的自身免疫性疾病。炎症、细胞募集和血管生成都是类风湿关节炎发病机制的重要组成部分。我们发现被称为岩藻糖基转移酶的酶在炎症性关节炎的这些过程中很重要。由于退伍军人患有许多血管生成重要的疾病，如伤口修复和肿瘤生长，这些研究可能在开发血管生成依赖型疾病的治疗方法方面具有广泛的适用性。此外，最初，这样的研究可能会为RA治疗开辟一个新的靶点家族。