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/摘要类风湿关节炎（RA）的特征是滑膜组织中的旺盛血管生成和白细胞浸润（ST）。我们已经表明，可溶性粘附分子E-选择蛋白（SE-选择素）诱导RA中的血管生成（参见Koch等人，自然376：517）。该分子介导血管生成的机制是通过在内皮细胞（EC）上结合siAllyl lewisx。炎症环境中存在的细胞因子可能会上调细胞表面粘附分子的产生。然后将这些分子脱落并诱导其他内皮细胞开始血管生成过程。 我们通过用发炎的人类衬里关节免疫小鼠来开发了一种新型的单克隆抗体（MAB）4A11。该mAb检测到在滑膜，皮肤，胸腺和淋巴器官中的ECS上表达的抗原。此外，这种抗原是可诱导的，并且在人类ra st中被上调。 MAB 4A11检测糖缀合物H-5-2（缩写H）和Lewisy-6（Ley），共同称为Ley/H。此外，Ley在结构上与Lex非常相似，Lex的siaLated形式是血管生成介质Se-Selectin的EC配体。我们发现，这些糖缀合物分别称为H-2G和Leyg的这些糖缀合物，或易于获得的葡萄糖类似物，在体内具有血管生成，介导单核细胞的募集和白细胞募集和白细胞粘附剂，以及诱导Matrix of Matrrix Metrix Metalloplopase-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，FUT1缺乏小鼠在血管生成和关节炎的发育中也缺乏。拟议研究的目的是检查FUT在炎症和血管生成中的作用。我们将确定：i）FUT1基因缺乏小鼠微血管ECS在体外表现出白细胞粘附和血管生成的改变； ii）FUT1基因缺乏小鼠在体内显示缺陷的白细胞募集； iii）小鼠在体内表现出缺陷的血管生成；如果IV）FUT1基因缺乏小鼠对体内关节炎的抗性具有抗性。 拟议的研究与VA任务非常相关，因为RA之类的关节炎是每年影响很大比例人口的非常普遍的条件。我们的结果还将对以白细胞募集和血管生成（例如伤口修复和实体瘤生长）为特征的状况具有潜在的治疗益处。每年的退伍军人人数越来越多。 因此，拟议的研究最初应阐明FUT是RA治疗的新靶标。检查FUT1缺乏的小鼠，其中ley/H的合成受损，为建立岩藻糖基化在炎症，关节炎和血管生成中的作用提供了难得的机会。这些研究应该为我们研究未来的FUT在人类RA中的作用，并有可能为RA治疗的全新目标开放。 公共卫生相关性： 项目叙事类风湿关节炎（RA）是一种影响1％人群的自身免疫性疾病。炎症，细胞募集和血管生成都是RA发病机理的重要组成部分。我们发现，称为岩藻糖基转移酶的酶对炎症性关节炎中的这些过程很重要。由于退伍军人患有多种疾病，其中血管生成很重要，例如伤口修复和肿瘤生长，这些研究可能对开发用于血管生成依赖性疾病的疗法具有广泛的适用性。此外，最初，诸如此类的研究可能会为RA治疗中的新目标开辟一系列。