IMMUNOREGULATORY FUNCTIONS OF THE ISOFORMS OF CD44

这项建议的目的是使申请者能够 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性结缔组织病。这个 申请者建议在五年内分两个阶段实现这一目标 一年期间。L阶段将主要致力于教学性学习和 获得开展研究所需的实验室技能 在Il阶段中提出。 第一阶段的具体目标如下：a.经历严格的 本系研究生院内的培训。免疫学博士，杜克 大学，以获得博士学位(博士学位)在免疫学上。为了 达到这一目标，申请者将于9月9日开始研究生学习。1993年 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，尤其是关于这些细胞在 类风湿性关节炎等疾病的免疫反应异常。在……里面 为了实现这一目标，将在跨膜上开展工作 蛋白多糖CD44。CD44及其配体透明质酸(HA)参与了 调节免疫反应的白细胞表面相互作用。 CD44不同亚型在白细胞上的差异表达 CD44可溶性形式的产生可能导致CD44有能力 调节CD3-T细胞受体介导的T淋巴细胞活化 调节细胞表面HA与白细胞的结合。的具体目标 L阶段的这一部分是：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 尤其是关于允许 透明质酸与CD44的结合。2.鉴定单抗和多克隆抗体 与CD44的特定亚型和/或功能表位结合的试剂 分子。 第二阶段的密集研究经验将利用这些试剂 以及关于不同CD44亚型在T细胞中的作用的知识 淋巴细胞活化及其与透明质酸结合能力的研究 CD44的表达及CD44在发病机制中的作用 类风湿性关节炎。第二阶段的具体目标是：1.界定 细胞外信号和细胞内分子事件 调节CD44与HA的结合，增强TCR介导的T细胞活化。2. 明确CD44在免疫反应中的调节作用并确定 单个CD44亚型的免疫调节功能。3.审查 类风湿关节炎患者异常免疫反应的研究 抗体试剂在相态土地上发展所获得的知识 CD44的调控。

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.