Regulation of T Cell and Mast Cell Function by DGKzeta

DGKzeta 对 T 细胞和肥大细胞功能的调节

• 批准号: 8093168
• 负责人: GARY A. KORETZKY
• 金额: $ 31.99万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8093168
• 关键词: 1,2-diacylglycerol; Address; Affect; Anaphylaxis; Animals; Arthritis; Biochemical; Biological Models; Catalytic Domain; Cell Line; Cell Surface Receptors; Cell physiology; Cells; Complex; Cutaneous; Data; Development; Diacylglycerol Kinase; Diglycerides; Enzymes; Event; Family member; Follow-Up Studies; Hematopoietic; IgE Receptors; Immune; Immune Cell Activation; Immunologics; Knockout Mice; Learning; Light; Maintenance; Mediating; Metabolism; Modeling; Mus; Pathway interactions; Phenotype; Phosphatidic Acid; Phosphatidylinositols; Play; Protein Kinase C; Regulation; Research Personnel; Role; Second Messenger Systems; Series; Signal Pathway; Signal Transduction; Structure; T cell regulation; T-Lymphocyte; Testing; Work; cell type; design; in vivo; intermolecular interaction; mast cell; mutant; novel strategies; programs; receptor; research study; response; second messenger; trafficking; tumor

DESCRIPTION (provided by applicant): Much has been learned in recent years regarding the biochemical events most critical for signal transduction mediated by numerous cell surface receptors on immune cells. A key second messenger is diacylglycerol (DAG), which is formed when engaged ITAM-bearing receptors activate the phosphatidylinositol cascade. DAG, in turn, stimulates at least two critical signaling cascades; the Ras pathway and several protein kinase C family members. Thus, understanding the formation of DAG and its metabolism is key to understanding immune cell activation. One means by which DAG function is terminated is the conversion of DAG to phosphatidic acid by DAG kinases (DGKs). This proposal focuses on DGKzeta, one of two DGKs expressed at high levels in hematopoietic cells. Our preliminary data indicate that DGKzeta is an important in vivo negative regulator of T cell and mast cell function. The experiments described in this proposal will make use of cell lines and genetically altered mice to investigate how DGKzeta serves this key role. Three specific aims will be pursued. First, we propose a cell biologic and biochemical analysis of DGKzeta to determine its subcellular localization and features most critical for affecting signaling pathways. The second aim will investigate the impact of DGKzeta deficiency on in vivo T cell function and the third aim will examine similar questions in the mast cell compartment. Both aims 2 and 3 will extend the structure/function analysis to determine features of this enzyme most essential for responses to immunologic challenges. We anticipate that this work will shed additional light on the complex regulation of T cell and mast cell function and will hopefully suggest novel approaches to modulate activity of these cell types.

描述（由申请人提供）：近年来，关于免疫细胞上众多细胞表面受体介导的信号转导最关键的生化事件已经了解了很多。关键的第二信使是二酰甘油 (DAG)，它是在 ITAM 受体激活磷脂酰肌醇级联反应时形成的。 DAG 反过来又会刺激至少两个关键的信号级联； Ras 途径和几个蛋白激酶 C 家族成员。因此，了解 DAG 的形成及其代谢是了解免疫细胞激活的关键。终止 DAG 功能的一种方法是通过 DAG 激酶 (DGK) 将 DAG 转化为磷脂酸。该提案重点关注 DGKzeta，它是造血细胞中高水平表达的两种 DGK 之一。我们的初步数据表明，DGKzeta 是 T 细胞和肥大细胞功能的重要体内负调节因子。该提案中描述的实验将利用细胞系和基因改造小鼠来研究 DGKzeta 如何发挥这一关键作用。将追求三个具体目标。首先，我们提出对 DGKzeta 进行细胞生物学和生化分析，以确定其亚细胞定位和对影响信号通路最关键的特征。第二个目标将研究 DGKzeta 缺陷对体内 T 细胞功能的影响，第三个目标将研究肥大细胞区室中的类似问题。目标 2 和 3 都将扩展结构/功能分析，以确定这种酶对于应对免疫挑战最重要的特征。我们预计这项工作将为 T 细胞和肥大细胞功能的复杂调节提供更多线索，并有望提出调节这些细胞类型活性的新方法。