PERIODONTAL DISEASE:ROLE OF ABERRANT Ig GLYCOSYLATION

牙周疾病：异常 Ig 糖基化的作用

• 批准号: 6910708
• 负责人: JIRI F MESTECKY
• 金额: $ 29.9万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6910708
• 关键词: PERIODONTAL; DISEASE; ROLE; ABERRANT; Ig

Principal Investigator/Program Director (Last, first, middle): Mestecky, Jiri DESCRIPTION: State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use oi the first person. This description is meant to serve as a succinct and accurate description of the proposed work when separated from the application. If the application is funded, this description, s is, will become public information. Therefore, do not include proprietarvlconfidentialinformation. DONOT EXCEEDTHE SP,ACE PROVIDED. Periodontal disease (PD) shares many common features with other human chronic inflammatory disease, such as rheumatoid arthritis, including production of autoantibodies, infiltration of lesions with plasma cells producing mainly IgG, and aberrant glycosylation of IgG-linked glycans. Particularly striking is the deficiency of galactose (Gal) in N-linked glycan side-chains on IgG molecules. Glycans have a profound effect on the biological activities of immunoglobulins (Ig). Deficiency of Gal residues renders such molecules pathogenic due to the fact that terminal N-acetylglucosamine residues, normally covered by Gal, became exposed and are recognized by the ubiquitous mannose-binding lectin resulting in the activation of complement with all the inflammatory consequences resulting in tissue damage. 13ased on considerable literature reports and our preliminary data, we propose to test the hypothesis that Ig-producing cells found in abundance in mononuclear cell infiltrates in PD secrete Ig molecules with aberrant slycosylation pattern of their glycan moieties. This in turn alters the biological properties of such Ig molecules with respect to their ability to activate complement and to interact with Fc receptors expressed on phagoclrtic cells resident in the inflamed lesions. Reduced glycosylation of Ig is likely to be due to the effect of cytokines locally produced by several cell types found in inflammatory lesions. Therefore, we propose the following specific aims: 1) Characterize the pattern of glycosylation aberrancies of Ig molecules in PD patients by reactivities with lectins highly specific for component monosaccharides and by direct carbohydrate analyses. 2) Determine the origin of aberrantly glycosylated Ig molecules by comparing glycosylation patterns of Ig in serum and lesions to determine whether Ig molecules with altered glycosylation are produced locally in the inflammatory lesions. 3) Determine if the aberrantly glycosylated Igs are specific for antigens of selected bacteria associated with PD. 4) Study mechanisms possibly involved in synthesis of Gal-deficient Ig.in PD patients and the biological activities of Ig molecules with altered glycans. Results of these studies will generate information concerning previously unexplored inflammatory pathways that participate in the development of PI). 'ERFORMANCESITE@) (organization,city, state) University of Alabama at Birmingham, Schools of Medicine and Dentistry, Birmingham, AL Columbia University, School of Dental and Oral Surgery, New York, NY KEY PERSONNEL ========================================Section End===========================================

首席调查员/计划主管（最后，第一，中间）：jiri的混血儿说明：说明该应用程序的广泛，长期目标和具体目标，引用了该项目的健康相关性。简单地描述实现这些目标的研究设计和方法。避免摘要过去的成就和第一人称的使用。此描述旨在作为与应用程序分离时对拟议工作的简洁而准确的描述。如果申请是资助的，则此描述为公共信息。因此，不包括专有文献。 Donot超过SP，ACE提供。 牙周疾病（PD）与其他人类慢性炎症性疾病（例如类风湿关节炎，包括自身抗体的产生，主要产生IgG的病变的浸润以及异常的IgG糖基化IgG连接聚糖）具有许多共同特征。特别惊人的是在IgG分子上N-连接的聚糖侧链中半乳糖（GAL）的缺乏。聚糖对免疫球蛋白（IG）的生物学活性具有深远的影响。 GAL残基的缺乏使该分子的致病性是由于末端N-乙酰葡萄糖残基（通常由GAL覆盖）暴露而来的，并被无处不在的甘露糖结合凝集素所认识到，导致互补的无效性互补，从而造成了所有炎症后果，从而导致组织损伤。 13基于大量文献报道和我们的初步数据，我们建议检验以下假设：在PD分泌的Ig分子中，具有异常的囊糖基化模式的单核细胞浸润中发现了IG产生细胞。反过来，这改变了这种Ig分子激活补体和与在发炎病变中居住的吞噬细胞上表达的FC受体相互作用的能力。 Ig的糖基化降低可能是由于炎症病变中几种细胞类型所产生的细胞因子的作用。因此，我们提出以下特定目的：1）表征PD患者Ig分子糖基化畸变的模式，该凝集素具有高度特异性的凝集素对成分单糖和直接碳水化合物分析。 2）通过比较血清和病变中Ig的糖基化模式来确定异常糖基化的Ig分子的起源，以确定在炎性病变中局部产生糖基化的Ig分子。 3）确定异常的糖基化Ig是否特异性对于与PD相关的选定细菌的抗原。 4）研究机制可能参与PD患者的GAL缺陷Ig.Ig的合成以及与聚糖改变的Ig分子的生物学活性。这些研究的结果将生成有关参与PI发展的先前未开发的炎症途径的信息。 'Erformancesite@）（组织，城市，州）阿拉巴马大学的伯明翰大学，伯明翰医学和牙科学院，伯明翰，伯明翰，哥伦比亚大学，哥伦比亚大学，牙科和口腔外科学院，纽约，纽约，纽约，密钥人员===================================================================== end ========================================