IMMUNOREGULATORY FUNCTIONS OF THE ISOFORMS OF CD44

CD44 异构体的免疫调节功能

• 批准号: 2077475
• 负责人: MARC C. LEVESQUE
• 金额: $ 6.05万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-15 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2077475
• 关键词: B lymphocyte; T cell receptor; T lymphocyte; antiserum; autoimmunity; biological signal transduction; clone cells; differentiation antigens; human subject; hyaluronate; immunoregulation; inflammation; laboratory mouse; laboratory rabbit; leukocyte activation /transformation; monoclonal antibody; monocyte; protein isoforms; protein structure function; receptor binding; receptor expression; rheumatoid arthritis

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发展 作为独立医学研究科学家的专业知识 基本的免疫学和自身免疫性结缔组织疾病。这 申请人建议在五个阶段以两个阶段完成这一目标 年期。 L期将主要致力于教学学习和 获得研究所必需的实验室技能 在IL期间提出。 第一阶段的具体目的是：A。进行严格 在杜克大学LMMUNOLOGY系研究生院内的培训 大学，获得LMMUnology博士学位（博士学位）。为了 达到这个目标，申请人将于1993年9月开始研究生院 并选择了将在此阶段完成的课程。 B.在淋巴细胞和单核细胞领域获得实验室专业知识 功能，尤其是关于这些细胞在 类风湿关节炎等疾病的异常免疫反应。在 为了实现这一目标，将在跨膜上进行工作 蛋白聚糖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各种同工型在白细胞和 生产CD44的可溶性形式可能会导致CD44的能力 调节CD3-T细胞受体介导的T淋巴细胞激活和TO 调节HA与白细胞的细胞表面结合。具体目的 相L的这一部分是：1。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的特定同工型和/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 淋巴细胞激活及其结合HA研究调节的能力 CD44表达并研究CD44在发病机理中的作用 类风湿关节炎。第二阶段的具体目的是：1。定义 细胞外信号和细胞内分子事件 调节CD44与HA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同工型的免疫介导的功能。 3。检查 类风湿关节炎的异常免疫反应利用 抗体试剂在相土地上开发了有关获得的知识 CD44的调节。