Immune Regulation by Deubiquitination

通过去泛素化进行免疫调节

基本信息

批准号：
9982199
负责人：
Michael Croft
金额：
$ 45万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-19 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982199
关键词：
Ablation Actin-Binding Protein Address Adoptive Transfer Affect Antibody Formation Antigens Autoantigens Autoimmune Diseases B-Cell Development B-Lymphocytes Biological Biological Assay Biological Process CD4 Positive T Lymphocytes Cell Communication Cell Count Cell physiology Cells Chronic Communicable Diseases Deubiquitinating Enzyme Deubiquitination Development Disease Enzymes Excision Exhibits FOXP3 gene Gene Expression Goals Helper-Inducer T-Lymphocyte Human IL4 gene Immune System Diseases Immune Tolerance Immune response Immune system Immunization In Vitro Inflammation Inflammatory Interleukin-4 Invaded Journals Knowledge Lung Lung Inflammation Lymphoid Tissue Mediating Modeling Molecular Mus Pathway interactions Peer Review Phenotype Play Process Production Protein Deficiency Proteins Pruritus Publishing Regulation Regulatory T-Lymphocyte Role Signal Transduction Solid Structure of germinal center of lymph node System T cell regulation T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Intervention Time Tissues Ubiquitin Ubiquitination Vaccination Virus Diseases antigen challenge autoinflammatory base cytokine design experimental study human disease immunoregulation in vivo migration named group novel novel therapeutic intervention pathogen protein biomarkers response success transcription factor ubiquitin-protein ligase

项目摘要

Project Summary Our long-term goal is to study the ubiquitin system in immune regulation. We initiated a new study of the deubiquitinating enzyme CYLD and found that deficiency of CYLD in T regulatory cells (Treg) caused chronic lung inflammation by increasing IL-4 production. These preliminary studies pointed to new mechanisms of CYLD regulation of Tregs, via modulating the cytokine production, and highlighted potential tissue-specific aspects of Treg function. Recently, we found that CYLD acts as a positive regulator in the differentiation of Treg to T follicular regulatory T cells (Tfr) in lymphoid tissues. These preliminary studies thus provide us with a solid basis for testing our central hypothesis that the ubiquitination/deubiquitination system plays a critical role in immune regulation via modulating different T cell subsets in tissue context-dependent manner. Here we plan to test this hypothesis by proposing two Specific Aims: Aim 1, to study CYLD in Treg regulation; and Aim 2, to study the role of CYLD in Tfr. The expected results will significantly advance our basic knowledge on the protein deubiquitination pathway in immune regulation, and will provide clues to therapeutic intervention of human diseases.

项目概要我们的长期目标是研究泛素系统在免疫调节中的作用。我们发起了一个去泛素化酶CYLD的新研究发现，T细胞中CYLD的缺乏调节细胞 (Treg) 通过增加 IL-4 的产生引起慢性肺部炎症。这些初步研究指出了 CYLD 调节 Tregs 的新机制，通过调节细胞因子的产生，并强调了潜在的组织特异性方面 Treg 功能。最近，我们发现 CYLD 在淋巴组织中 Treg 分化为 T 滤泡调节性 T 细胞 (Tfr)。这些因此，初步研究为我们检验中心假设提供了坚实的基础泛素化/去泛素化系统在免疫调节中发挥着关键作用通过以组织环境依赖性方式调节不同的 T 细胞亚群。在这里我们计划通过提出两个具体目标来检验这一假设：目标 1，研究 CYLD Treg 调节；目标 2，研究 CYLD 在 Tfr 中的作用。预期结果将显着提高了我们对蛋白质去泛素化途径的基础知识免疫调节，将为人类疾病的治疗干预提供线索。