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IMMUNOREGULATORY FUNCTIONS OF THE ISOFORMS OF CD44

CD44 异构体的免疫调节功能

基本信息

批准号：
2517399
负责人：
MARC C. LEVESQUE
金额：
$ 8.66万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-09-15 至 1999-08-31
项目状态：
已结题

项目摘要

The objective of this proposal is to enable the applicant to develop expertise as an independent medical research scientist in the fields of basic immunology and autoimmunemediated connective tissue disease. The applicant proposes to accomplish this objective in two phases over a five year period. Phase l will be devoted primarily to didactic learning and the acquisition of laboratory skills necessary to carry out the research proposed in phase Il. The specific aims of phase I are the following: A. To undergo rigorous training within the Graduate School in the Dept. of lmmunology, Duke University, to earn a doctoral degree (Ph.D.) in lmmunology. In order to attain this goal, the applicant will begin graduate school in Sept. 1993 and has selected coursework that will be accomplished during this phase. B. To attain laboratory expertise in the area of lymphocyte and monocyte function, especially with regards to the role that these cells play in the abnormal immune response of diseases such as rheumatoid arthritis. In order to attain this goal, work will be carried out on the transmembrane proteoglycan CD44. CD44 and its ligand hyaluronan (HA) are involved in leukocyte cell surface interactions that modulate the immune response. Differential expression of the various isoforms of CD44 on leukocytes and production of a soluble form of CD44 likely lead to the ability of CD44 to modulate CD3-T cell receptor mediated T lymphocyte activation and to regulate cell surface binding of HA to leukocytes. The specific aims of this part of phase l are: 1. To characterize the CD44 Isoforms present on human peripheral blood T lymphocytes, B lymphocytes and monocytes especially with regards to the molecular characteristics that allow binding of HA to CD44. 2. Characterize monoclonal and polyclonal antibody reagents that bind to specific isoforms and/or functional epitopes of CD44 molecules. The intensive research experience in phase II will utilize the reagents and knowledge gained about the role of the different CD44 isoforms in T lymphocyte activation and their ability to bind HA to study the regulation of CD44 expression and to study what role CD44 plays in the pathogenesis of rheumatoid arthritis. The specific aims of phase II are: 1. To define the extracellular signals and the intracellular molecular events that regulate CD44 binding to HA and enhance TCR-mediated T cell activation. 2. To define the regulatory role of CD44 in the immune response and determine the immune-mediated functions of the individual CD44 isoforms. 3. Examine the abnormal immune response in rheumatoid arthritis utilizing the antibody reagents developed in phase land the knowledge gained about the regulation of CD44.

该提案的目的是使申请人能够开发作为独立医学研究科学家在以下领域的专业知识基础免疫学和自身免疫介导的结缔组织疾病。这申请人建议在五年内分两个阶段实现这一目标年期间。第一阶段将主要致力于教学学习和获得进行研究所需的实验室技能在第二阶段提出。第一阶段的具体目标如下： A. 进行严格的在杜克大学免疫学系研究生院接受培训大学，获得免疫学博士学位（Ph.D.）。为了为了实现这一目标，申请人将于 1993 年 9 月开始研究生学习并选择了将在此阶段完成的课程作业。 B. 获得淋巴细胞和单核细胞领域的实验室专业知识功能，特别是这些细胞在类风湿性关节炎等疾病的异常免疫反应。在为了实现这一目标，将在跨膜方面开展工作蛋白多糖CD44。 CD44 及其配体透明质酸 (HA) 参与白细胞细胞表面相互作用调节免疫反应。 CD44 的各种亚型在白细胞和淋巴细胞上的差异表达 CD44 可溶形式的产生可能导致 CD44 能够调节 CD3-T 细胞受体介导的 T 淋巴细胞活化并调节 HA 与白细胞的细胞表面结合。具体目标第 l 阶段的这一部分是： 1. 表征 CD44 亚型人外周血T淋巴细胞、B淋巴细胞和单核细胞特别是关于允许的分子特征 HA 与 CD44 的结合。 2. 表征单克隆和多克隆抗体与 CD44 的特定异构体和/或功能表位结合的试剂分子。第二阶段的深入研究经验将利用试剂以及关于不同 CD44 同工型在 T 中的作用的知识淋巴细胞活化及其与HA结合能力的调节研究 CD44表达的变化并研究CD44在发病机制中发挥的作用类风湿性关节炎。第二阶段的具体目标是： 1. 定义细胞外信号和细胞内分子事件调节 CD44 与 HA 的结合并增强 TCR 介导的 T 细胞活化。 2. 定义 CD44 在免疫反应中的调节作用并确定单个 CD44 同工型的免疫介导功能。 3. 检查类风湿关节炎中的异常免疫反应利用阶段开发的抗体试剂获得了关于 CD44的调节。