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: 7797230
• 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 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797230
• 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）： 风湿性关节炎（RA）的特征是滑膜组织（ST）中血管生成旺盛和白细胞浸润。我们已经表明可溶性粘附分子E-选择素（sE-选择素）诱导RA中的血管生成（参见Koch et.等人，Nature 376：517）。该分子介导血管生成的机制是通过结合内皮细胞（EC）上的唾液酸化Lewisx。很可能存在于炎症环境中的细胞因子上调细胞表面粘附分子的产生。然后这些分子脱落并诱导其他内皮细胞开始血管生成过程。 我们已经开发了一种新的单克隆抗体（mAb）4A 11免疫小鼠与细胞从发炎的人ST衬里关节。该mAb检测滑膜、皮肤、胸腺和淋巴器官中EC上表达的抗原。此外，该抗原在人RA ST中是可诱导的并上调。MAb 4A 11检测糖缀合物H-5-2（缩写为H）和Lewisy-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。我们已经发现，这些糖缀合物，或这些糖缀合物的容易获得的葡萄糖类似物，分别称为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粘附，以及诱导RA ST成纤维细胞产生基质金属蛋白酶-2。 Ley和H的合成由岩藻糖基转移酶（称为futs）控制。我们的初步数据表明，fut 1缺陷小鼠在血管生成和关节炎的发展方面也有缺陷。这项研究的目的是研究futs在炎症和血管生成中的作用。我们将确定：I）如果fut 1基因缺陷小鼠微血管EC在体外显示白细胞粘附和血管生成的改变; II）fut 1基因缺陷小鼠在体内显示白细胞募集缺陷; III）小鼠在体内显示血管生成缺陷;以及IV）如果fut 1基因缺陷小鼠在体内对关节炎发展具有抗性。 拟定研究与VA使命非常相关，因为关节炎（如RA）是每年影响大部分人群的常见疾病。我们的研究结果还将对以白细胞募集和血管生成为特征的疾病（如伤口修复和实体瘤生长）具有潜在的治疗益处。每年都有越来越多的退伍军人受到恶性肿瘤的折磨，我们的研究结果最终也可能使这些退伍军人受益。 因此，拟议的研究应该首先阐明futs作为RA治疗中可能的新靶点。检查fut 1缺陷小鼠，其中Ley/H的合成受损，提供了一个难得的机会来建立岩藻糖基化在炎症，关节炎和血管生成中的作用。这些研究应该为我们将来研究futs在人类RA中的作用奠定基础，并可能为治疗RA开辟一个全新的靶点家族。 公共卫生相关性： 风湿性关节炎（RA）是一种自身免疫性疾病，影响1%的人口。炎症、细胞募集和血管生成都是RA发病机制的重要组成部分。我们发现岩藻糖基转移酶对炎症性关节炎的这些过程很重要。由于退伍军人患有许多血管生成很重要的疾病，如伤口修复和肿瘤生长，这些研究可能对开发血管生成依赖性疾病的疗法具有广泛的适用性。此外，最初，这些研究可能会在RA治疗中开辟一个新的靶点家族。