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：
8848754
负责人：
STEPHEN C BUNNELL
金额：
$ 63.64万
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 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8848754
关键词：
Adaptor Signaling Protein Address Alleles Anti-Inflammatory Agents 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-κB transcription factors is required to mount immune responses to pathogens and for the normal homeostasis of the immune system. Conversely, excessive NF-κB-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-κB 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 IKKγ that may be involved in delivery of IKKγ to TCR microclusters and/or its down-regulation. However, a number of important questions remain to be answered regarding the sub-cellular regulation of IKKγ 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-κB activation for therapeutic purposes. We hypothesize that TCR/CD28 activation of the classical NF-κB pathway requires complex sub-cellular regulation of the adaptor protein IKKγ/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-κB转录因子的适当调节以对病原体进行免疫反应对免疫系统的或MAL稳态。肿瘤的形成对NF-κB家族转录因子很重要虽然描述的后翻译修饰和泛素化。。重要的是，如果我们将最终的dismenterdge运用到治疗目的的NF-κB激活中因此，在AIM 1中，我们将确定ZAP70和LCK复合物对TCR微簇的作用。 s）包含全部和活跃的IKK复合物