PERIODONTAL DISEASE:ROLE OF ABERRANT Ig GLYCOSYLATION

首席研究员/项目主管（最后、第一、中间）：Mestecky， Jiri描述：陈述申请的广泛、长期目标和具体目标，并参考项目与健康的关系。简要描述为实现这些目标的研究设计和方法。避免总结过去的成就和使用第一人称。当与应用程序分离时，此描述旨在作为对所建议工作的简洁而准确的描述。如果应用程序获得资助，则此描述将成为公共信息。因此，不要包含专有机密信息。不要超过规定的标准。牙周病（PD）与其他人类慢性炎症疾病（如类风湿关节炎）有许多共同特征，包括自身抗体的产生，主要产生IgG的浆细胞浸润病变，以及IgG连接聚糖的异常糖基化。尤其引人注目的是在IgG分子的n链聚糖侧链中缺乏半乳糖（Gal）。聚糖对免疫球蛋白（Ig）的生物活性有深远的影响。由于通常被Gal覆盖的末端n -乙酰氨基葡萄糖残基暴露并被无处不在的甘露糖结合凝集素识别，导致补体活化，所有炎症后果导致组织损伤，因此缺乏Gal残基使这些分子具有致病性。基于大量的文献报道和我们的初步数据，我们提出验证一个假设，即在PD中浸润的单核细胞中大量发现的产igg细胞分泌具有异常糖基化模式的Ig分子。这反过来又改变了这些Ig分子的生物学特性，即它们激活补体的能力，以及与炎性病变中吞噬细胞上表达的Fc受体相互作用的能力。Ig糖基化的降低可能是由于炎性病变中几种细胞类型局部产生的细胞因子的影响。因此，我们提出以下具体目标：1)通过与单糖成分高度特异性凝集素的反应和直接碳水化合物分析来表征PD患者Ig分子糖基化异常的模式。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Ig分子的来源，以确定糖基化改变的Ig分子是否在炎症病变中局部产生。3)确定异常糖基化的Igs是否对与PD相关的选定细菌抗原具有特异性。4)研究可能参与gal缺陷Ig合成的机制。改变聚糖的Ig分子的生物学活性。这些研究的结果将提供有关参与PI发展的先前未被探索的炎症途径的信息。“ERFORMANCESITE@)(组织、城市、国家)伯明翰阿拉巴马大学,医科和牙科学校,伯明翰,哥伦比亚大学,学校的牙科和口腔外科,纽约,纽约关键人员 ======================================== 节结束 ===========================================

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===========================================