Mechanisms of protein ubiquitination in regulating airway inflammation

蛋白质泛素化调节气道炎症的机制

基本信息

批准号：
7582564
负责人：
YUN-CAI LIU
金额：
$ 41.18万
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：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7582564
关键词：
Ablation Accounting Affect Allergic Antigens Asthma Autoimmune Process Autoimmunity Biochemical Biological Models Breathing CD4 Positive T Lymphocytes Cell physiology Cells Chronic Classification Data Developed Countries Developing Countries Development Disease Dose Eosinophilia Extrinsic asthma Generations Genes Genetic Goals Human IgE Immune response In Vitro Inflammatory Inflammatory Response Injection of therapeutic agent Interleukin-13 Interleukin-4 Interleukin-5 Interleukin-6 Knowledge Link Lung Maintenance Mediating Modeling Mucous body substance Mus Mutant Strains Mice Pathogenesis Phenotype Play Population Process Production Property Proteins Pruritus Reaction Regulation Research Respiratory System Respiratory tract structure Role Self Tolerance Serum Signal Pathway Signal Transduction Skin T-Cell Activation T-Lymphocyte Testing Th2 Cells Transforming Growth Factors Ubiquitination Wild Type Mouse airway hyperresponsiveness airway inflammation airway remodeling anergy attenuation cytokine design genetic analysis in vitro Model in vivo novel therapeutic intervention public health relevance receptor research study response ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to study the mechanisms of protein ubiquitination in the regulation of immune responses. Allergic asthma is a chronic inflammatory disease of the airways featured by the elevated serum immunoglogulin E (IgE) concentrations, airway hyperresponsiveness, excessive airway mucus production, lung eosinophilia, and airway remodeling. Differentiation of CD4+ T cells into T helper type 2 (Th2) cells renders them to produce Th2 type cytokines to drive asthmatic pathogenesis. The Th2-mediated immune responses are counterbalanced by tolerogenic mechanisms that keep the excessive reaction under control. One of the tolerance mechanisms involves regulatory T cells (Tregs) that limit the allergic responses. Transforming growth factor (TGF)-2 is critically involved in the generation and function of Tregs. Using both in vivo and in vitro model systems, we recently obtained preliminary data suggesting that the E3 ubiquitin ligase Itch plays an important role in the TGF-2-induced expression of Foxp3 and Treg- mediated proliferative inhibition. The new preliminary data allow us to formulate a hypothesis that the E3 ubiquitin ligase Itch is an important regulator in TGF-2 signaling, which is linked to TGF-2-induced Treg generation. Such regulation of T cell function underlies the mechanistic involvement of Itch in the development of Th2-mediated allergic responses. We plan to test this hypothesis by proposing detailed experiments to elucidate the intracellular signaling pathways modulated by Itch-induced protein ubiquitination, with a combination of both genetic and biochemical approaches. Such studies will help to design novel therapeutic interventions for allergic diseases. PUBLIC HEALTH RELEVANCE Mechanisms of protein ubiquitination in regulating airway inflammation Narrative Asthma is on the rise in both industrialized and developing countries, which affects over 20 million people in the US alone. Allergic asthma is a chronic inflammatory disease of the airways. Differentiation of CD4+ T cells into T helper type 2 (Th2) cells renders them to produce cytokines, which are critical to drive asthmatic pathogenesis. This proposal is to study the regulatory mechanisms to control excessive T cell activation. The knowledge gained from the proposed research will help design new therapeutic approaches for human allergic diseases.

描述（由申请人提供）：我们的长期目标是研究免疫反应调节中蛋白质泛素化的机制。过敏性哮喘是一种慢性炎症性疾病的气道疾病，其血清免疫蛋白E（IgE）浓度升高，气道高反应性，过度气道粘液产生，肺嗜酸性粒细胞增生和气道重塑。将CD4+ T细胞分化为T型辅助2型（TH2）细胞使它们产生Th2型细胞因子以驱动哮喘发病机理。 Th2介导的免疫反应与耐受性反应的耐受性机制相抵消。耐受性机制之一涉及限制过敏反应的调节T细胞（Tregs）。转化生长因子（TGF）-2与Treg的产生和功能至关重要。使用体内和体外模型系统，我们最近获得了初步数据，表明E3泛素连接酶瘙痒在TGF-2诱导的FOXP3表达和Treg介导的增殖抑制中起着重要作用。新的初步数据使我们能够提出一个假设，即E3泛素连接酶迭代是TGF-2信号中的重要调节剂，该调节剂与TGF-2诱导的Treg生成有关。 T细胞功能的这种调节是瘙痒在Th2介导的过敏反应的发展中的机械参与。我们计划通过提出详细的实验来检验这一假设，以阐明由瘙痒诱导的蛋白质泛素化调节的细胞内信号通路，并结合了遗传和生化方法。此类研究将有助于设计针对过敏性疾病的新型治疗干预措施。蛋白质泛素化在调节气道炎症叙事中的蛋白质泛素化机制在工业化和发展中国家都在上升，仅在美国就影响了超过2000万人。过敏性哮喘是气道的慢性炎症性疾病。将CD4+ T细胞分化为T辅助2型（TH2）细胞的细胞产生细胞因子，这对于驱动哮喘发病机理至关重要。该建议是研究控制过度T细胞激活的调节机制。从拟议的研究中获得的知识将有助于为人类过敏性疾病设计新的治疗方法。