Immune Regulation by Deubiquitination

通过去泛素化进行免疫调节

• 批准号: 9788250
• 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
• 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/9788250
• 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

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.

项目摘要 我们的长期目标是研究免疫调节中的泛素系统。我们发起了一个 一项新的去泛素化酶CYLD的研究发现，T细胞CYLD的缺乏， 调节细胞（Treg）通过增加IL-4的产生而引起慢性肺部炎症。 这些初步的研究指出了CYLD调节TGFAP的新机制， 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作为一个积极的调节剂，在 在淋巴组织中Treg向T滤泡调节性T细胞（Tfr）的分化。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起着关键作用 通过以组织环境依赖性方式调节不同的T细胞亚群。这里我们 我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， 目的2：研究CYLD在Tfr中的作用。预期结果将 显著推进我们对蛋白质去泛素化途径的基础知识， 免疫调节，并将为人类疾病的治疗干预提供线索。