IMMUNOREGULATORY FUNCTIONS OF THE ISOFORMS OF CD44

本建议书的目的是使申请人能够发展 作为一名独立的医学研究科学家， 基础免疫学和自身免疫介导的结缔组织病。的 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式学习， 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：经过严格 本系研究生院内的培训。免疫学的最新进展，杜克 大学，以获得博士学位（博士）在免疫学上。为了 达到这一目标，申请人将开始研究生院在9月。1993 并选择了将在此阶段完成的课程。 B。获得淋巴细胞和单核细胞领域的实验室专业知识 功能，特别是关于这些细胞在 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 蛋白多糖CD44。CD44及其配体透明质酸（HA）参与了 调节免疫应答的白细胞表面相互作用。 白细胞上CD44各种亚型的差异表达， 可溶形式的CD44的产生可能导致CD44的能力， 调节CD3-T细胞受体介导的T淋巴细胞活化， 调节HA与白细胞的细胞表面结合。的具体目标 阶段l的这一部分是：1。为了表征存在于 人外周血T淋巴细胞、B淋巴细胞和单核细胞 特别是在分子特征方面， HA与CD44的结合。2.表征单克隆和多克隆抗体 与CD44的特异性同种型和/或功能性表位结合的试剂 分子。 第二阶段的深入研究经验将利用这些试剂 以及获得的关于不同CD44亚型在T细胞中的作用的知识， 淋巴细胞活化及其结合HA的能力，以研究调节 研究CD44在肿瘤发病中的作用 类风湿性关节炎第二阶段的具体目标是：1.以限定 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. 明确CD44在免疫应答中的调节作用， 单个CD44同种型的免疫介导功能。3.审查 类风湿性关节炎中的异常免疫应答利用 抗体试剂开发阶段土地获得的知识， 调节CD44。

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.