STRUCTURE AND FUNCTION OF THE HUMAN DPPIV/CD26 MOLECULE

人 DPPIV/CD26 分子的结构和功能

• 批准号: 3200109
• 负责人: Chikao Morimoto
• 金额: $ 15.4万
• 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/3200109
• 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.

酶二肽肽酶IV（DPPIV）是一种完整的膜蛋白 其广泛分布于哺乳动物组织中，包括肝，肾， 肠刷状缘膜和胎盘。 DPPIV还表示 在静息T细胞亚群上的水平非常低。 DPPIV阳性 T细胞几乎负责所有的IL-2分泌，并且在 启动B细胞的免疫球蛋白合成。 最近的证据表明， 提出T细胞的CD 26抗原实际上是DPPIV， CD 26在T细胞活化中起关键作用。 还有许多问题有待澄清 关于这种蛋白质在哺乳动物系统中的复杂功能， 其假定的生理底物和/或配体。 的主要目标 这一建议是为了确定结构和功能关系， 在粘附、胞外酶和信号转导功能之间， 人DPPIV/CD 26分子。 为了实现这一目标，我们将首先开发一个大型面板或 针对DPPIV/CD 26的不同表位的单克隆抗体， 包括抑制DPPIV酶活性的mAb。 这些将被用作 识别功能重要领域的工具。 二是 确定DPPIV/CD 26在细胞外基质细胞中的作用 相互作用和细胞迁移。 第三，我们将确定功能 DPPIV/CD 26在利用CD 26的信号转导和免疫功能中的作用 转染的Jurkat白血病T细胞系，突变的CD 26- H9 T细胞系， 和外周血T细胞作为模型系统。 第四，我们将准备 可溶性重组DPPIV/CD 26分子，并测定它们对 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/CD 26的天然底物/配体。 最后，我们将确定 人DPPIV/CD 26结合分子的功能和结构， 第43页。 以上资料应有助我们进一步了解 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一个新的类的合理设计 在调节中充当特异性拮抗剂或激动剂的药物 细胞粘附、迁移和信号转导以及其他 DPPIV/CD 26的功能。 这将对治疗有意义， 恶性肿瘤、自身免疫性疾病和免疫缺陷的治疗 艾滋病等疾病。