STRUCTURE AND FUNCTION OF THE HUMAN DPPIV/CD26 MOLECULE

人 DPPIV/CD26 分子的结构和功能

• 批准号: 2096730
• 负责人: Chikao Morimoto
• 金额: $ 14.62万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2096730
• 关键词: CD antigens; T lymphocyte; antisense nucleic acid; biological signal transduction; cell adhesion; cell migration; chemical binding; cytokine; enzyme activity; extracellular matrix proteins; fusion gene; human tissue; laboratory mouse; membrane proteins; monoclonal antibody; peptidyl dipeptidase; protein biosynthesis; protein structure function; recombinant proteins; tissue /cell culture

The enzyme dipeptidy peptidase IV (DPPIV) is an integral membrane protein which is widely distributed in mammalian tissues including liver, kidney, intestinal brush border membrane and placenta. DPPIV is also expressed at very low levels on a subset of resting T cells. The DPPIV positive T cells account for almost all IL-2 secretion and are important in initiating immunoglobulin synthesis by B cells. Recent evidence has been presented that the CD26 antigen of T cells is actually a DPPIV and that CD26 plays a key role in T cell activation. Much remains to be clarified regarding the complex functions of this protein in mammalian systems and its putative physiological substrates and/or ligands. The major goal of this proposal is to define the structural and functional relationships between the adhesion, ectoenzymatic and signal transducing functions of the human DPPIV/CD26 molecule. To accomplish this goal, we will first develop a large panel or monoclonal antibodies directed against different epitopes of DPPIV/CD26, including mAbs inhibiting DPPIV enzyme activity. These will be used as tools in identifying functionally important domains. Second, we will determine the role of DPPIV/CD26 in extracellular matrix-cell interactions and cell migration. Third, we will determine the function of DPPIV/CD26 in signal transduction and immune function utilizing CD26 transfected Jurkat leukemic T cell lines, a mutant CD26- H9 T cell line, and peripheral blood T cells as model systems. Fourth, we will prepare soluble recombinant DPPIV/CD26 molecules and determine their effects on various biological activities including cytokine production, cell adhesion, cell activation and migration. In addition, we will identify the natural substrates/ligands of DPPIV/CD26. Finally, we will determine the function and structure of the human DPPIV/CD26 association molecule, p43. The above information should help us to further understand the mechanisms of tumor invasion or metastasis, and the inflammatory process. Moreover, these studies may lead to the rational design of a novel class of drugs that act as specific antagonists or agonists in the regulation of cell adhesion, migration and signal transduction as well as other functions of DPPIV/CD26. This would have therapeutic implications for treatment of malignant tumors, autoimmune disorders, and immunodeficiency diseases such as AIDS.

二肽肽酶 IV (DPPIV) 是一种整合膜蛋白 广泛分布于哺乳动物的肝、肾、 肠刷状缘膜和胎盘。 DPPIV 也表达为 静息 T 细胞子集上的水平非常低。 DPPIV 阳性 T 细胞几乎负责所有 IL-2 的分泌，并且在 启动 B 细胞合成免疫球蛋白。 最近的证据已经 提出 T 细胞的 CD26 抗原实际上是 DPPIV，并且 CD26 在 T 细胞激活中发挥关键作用。 还有很多事情有待澄清 关于这种蛋白质在哺乳动物系统中的复杂功能和 其假定的生理底物和/或配体。 主要目标是 该提案旨在定义结构和功能关系 粘附、胞外酶和信号转导功能之间 人 DPPIV/CD26 分子。 为了实现这个目标，我们首先要开发一个大面板或者 针对 DPPIV/CD26 不同表位的单克隆抗体， 包括抑制 DPPIV 酶活性的 mAb。 这些将用作 识别功能重要领域的工具。 其次，我们将 确定 DPPIV/CD26 在细胞外基质细胞中的作用 相互作用和细胞迁移。 三、我们要确定功能 DPPIV/CD26 在信号转导和利用 CD26 的免疫功能中的作用 转染的 Jurkat 白血病 T 细胞系，一种突变型 CD26-H9 T 细胞系， 和外周血T细胞作为模型系统。 四、我们要准备 可溶性重组 DPPIV/CD26 分子并确定其对 各种生物活性，包括细胞因子的产生、细胞 粘附、细胞活化和迁移。 此外，我们将确定 DPPIV/CD26 的天然底物/配体。 最后，我们将确定 人DPPIV/CD26缔合分子的功能和结构， 第 43 页。 以上信息应该可以帮助我们进一步了解 肿瘤侵袭或转移的机制以及炎症过程。 此外，这些研究可能会导致新课程的合理设计 在监管中充当特定拮抗剂或激动剂的药物 细胞粘附、迁移和信号转导等 DPPIV/CD26 的功能。 这将对以下疾病产生治疗意义： 治疗恶性肿瘤、自身免疫性疾病和免疫缺陷 艾滋病等疾病。