Biochemical and Spatial Regulation of IKKg/NEMO During T Cell Activation

T 细胞激活过程中 IKKg/NEMO 的生化和空间调节

基本信息

批准号：
8672595
负责人：
STEPHEN C BUNNELL
金额：
$ 63.38万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-06 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8672595
关键词：
Adaptor Signaling Protein Address Alleles Anti-Inflammatory Agents Anti-inflammatory Antigen Receptors Antigens Autoimmune Diseases B-Lymphocytes Biochemical Biological Biological Assay CD27 Antigens CD28 gene Cells Cellular Structures Chimera organism Chronic Complex Data Development Down-Regulation Elements Event Family Fluorescence Resonance Energy Transfer Health Homeostasis Image Immune Immune response Immune system Individual Inflammation Inflammatory Knowledge LCP2 gene Laboratories Lead Light Malignant Neoplasms Maps Mediating Nature Pathway interactions Phosphorylation Play Polyubiquitin Post-Translational Protein Processing Protein Family Protein Tyrosine Kinase Proteins Receptor Signaling Recruitment Activity Regulation Relative (related person)Reporter Role Series Signal Pathway Signal Transduction Signaling Protein Structure Synapses T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Ubiquitination base cell growth regulation cell type conserved helix-loop-helix ubiquitous kinase inhibitor/antagonist mutant novel pathogen protein complex receptor scaffold spatial relationship spatiotemporal transcription factor transmission process tumor

项目摘要

DESCRIPTION (provided by applicant): Proper regulation of NF-?B transcription factors is required to mount immune responses to pathogens and for the normal homeostasis of the immune system. Conversely, excessive NF- ?B-dependent inflammation can help to drive the development of autoimmune disease and the formation of tumors. In this light, it is important to know how NF-?B family transcription factors are controlled by signaling through the different types of receptors that impinge on this pathway. During T cell activation by antigen, TCR and CD28, and numerous signaling proteins, are reorganized into distinct structures while undergoing well-described post-translational modifications, such as phosphorylation and ubiquitination. Although the IKK complex accumulates in the TCR-rich domain at the center of the immune synapse, receptor signals are initiated by TCR 'microclusters' in the periphery of the contact. We have found that the IKK complex is rapidly recruited to signaling microclusters containing the TCR and Zap70, but not SLP-76. Our imaging studies have also revealed additional pools of IKK? that may be involved in delivery of IKK? to TCR microclusters and/or its down-regulation. However, a number of important questions remain to be answered regarding the sub-cellular regulation of IKK? and its role in T cell activation. Carrying out such studies is important, if we are to eventually exploit this knowledge to manipulate TCR-mediated NF-?B activation for therapeutic purposes. We hypothesize that TCR/CD28 activation of the classical NF-?B pathway requires complex sub-cellular regulation of the adaptor protein IKK?/NEMO. Thus, in Aim 1, we will determine the role of Zap70 and Lck in recruitment of the IKK complex to TCR microclusters. In Aim 2, we will define the role of Carma1 and associated proteins in spatial regulation of the IKK complex. Finally, in Aim 3 we will define the sub-cellular compartment(s) containing total and active IKK complexes

描述（由申请人提供）：对NF-？B转录因子的适当调节以安装对病原体的免疫反应以及免疫系统的正常稳态。相反，过度的NF-依赖性炎症可以帮助推动自身免疫性疾病的发展和肿瘤的形成。从这个角度来看，重要的是要知道如何通过通过在该途径上造成的不同类型的受体发出信号来控制NF-？B家族转录因子。在T细胞激活期间，抗原，TCR和CD28以及许多信号蛋白被重新组织为不同的结构，同时经过了良好描述的翻译后修饰，例如磷酸化和泛素化。尽管IKK络合物在免疫突触中心的富含TCR域中积聚，但在接触的外围的TCR“微量群体”启动了受体信号。我们发现，IKK复合物迅速募集到包含TCR和ZAP70的信号微群体，但不募集SLP-76。我们的成像研究还揭示了IKK的其他池？那可能涉及IKK的交付？到TCR微群和/或其下调。但是，关于IKK的亚细胞调节，还有许多重要的问题要回答？及其在T细胞激活中的作用。进行这样的研究是重要的是，如果我们最终要利用这些知识来操纵TCR介导的NF-？b激活用于治疗目的。我们假设经典NF-途径的TCR/CD28激活需要对适配器蛋白IKK的复杂亚细胞调节？/NEMO。因此，在AIM 1中，我们将确定ZAP70和LCK在IKK复合物募集到TCR微量群体中的作用。在AIM 2中，我们将定义CARMA1和相关蛋白在IKK复合物的空间调节中的作用。最后，在AIM 3中，我们将定义包含总IKK复合物的亚细胞室