Ubiquitin complexes that limit inflammation and cytokine production in allergy

泛素复合物可限制过敏中的炎症和细胞因子的产生

• 批准号: 8872402
• 负责人: Paula Maria Oliver
• 金额: $ 42万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8872402
• 关键词: Affect; Allergens; Allergic Disease; Allergic inflammation; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Atopic Dermatitis; Biochemical; Biological Assay; Biology; Cell Differentiation process; Cells; Cellular biology; Charge; Chronic; Complex; Data; Defect; Disease; Eosinophilia; Family; Family member; Food; Functional disorder; Goblet Cells; Health; Human; Hyperplasia; Hypersensitivity; Immune response; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Interleukin-13; Interleukin-4; Interleukin-5; Isotope Labeling; Left; Life; Lung; Lung Inflammation; Mediating; Mus; Mutation; Pathogenicity; Pathway interactions; Patients; Peptides; Procedures; Process; Production; Proteins; Proteomics; Publishing; Research Personnel; Role; Skin; Symptoms; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Ubiquitin; Ubiquitin-Conjugating Enzymes; Work; airway hyperresponsiveness; base; cytokine; design; genome wide association study; immunopathology; in vivo; insight; man; mouse model; novel; novel therapeutic intervention; pathogen; prevent; research study; therapy design; tool; transcription factor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Chronic allergic diseases, such as asthma, affect millions of individuals world wide and can be life threatening. Despite new therapeutic approaches, the incidence of asthma is on the rise and many patients' symptoms are not adequately controlled. These diseases are often driven by allergen-specific T cells. While the role of CD4+ TH2 cells and their production of IL-4, IL-5 and IL-13 has been well-established, what causes these cytokine producing T cells to lose control and drive inflammation in the absence of pathogen invasion is not well understood. Genome wide association studies (GWAS) studies have identified defects in pathways that regulate cytokine production by these TH2 cells. One pathway that regulates TH2 production and lung inflammation in both mouse and man involves the E3 ubiquitin ligase Itch. We have identified an E3 ubiquitin ligase adaptor, Nedd4-family interacting protein 1 (Ndfip1), that activates several E3 ubiquitin ligases, including Itch, to limit TH2 cell differentiation and proinflammatory cytokine production. Our published data suggest that Ndfip1 prevents T cell activation, TH2 differentiation and consequent lung inflammation characterized by goblet cell hyperplasia and eosinophilia. Our preliminary data reveal the mechanistic underpinnings of how Ndfip1 activates E3 ubiquitin ligases like Itch. These results may define a new paradigm for activation of Itch as well as other Nedd4-family members. Based on these studies, we have designed a novel approach for therapeutic activation of these E3 ligases to treat allergic disease. This proposal is centered on testing two interrelated hypotheses. We hypothesize that Ndfip1 relieves autoinhibition of Itch to limit proinflammatory cytokine production in T cells. We hypothesize that therapeutic mimics of Ndfip1 can be used to activate ubiquitylation cascades to limit TH2 cytokine production and to reduce lung inflammation. Experiments described in this proposal will determine the key biochemical features that allow Ndfip1 to trigger Itch activation, and test whether Ndfip1 peptides can be used to limit proinflammatory cytokine production in TH2 cells. Additionally, using quantitative proteomics, we will determine the underlying mechanisms of how Ndfip1 regulates proinflammatory cytokine production in TH2 cells. While this proposal is focused on testing the therapeutic potential using mouse models of T cell-mediated inflammation in the lung, these data could have broad implications for designing therapies to treat allergic diseases such as asthma.

描述（由申请人提供）：慢性过敏性疾病，例如哮喘，影响着全世界数百万人，并可能危及生命。尽管有新的治疗方法，哮喘的发病率仍在上升，并且许多患者的症状没有得到充分控制。这些疾病通常是由过敏原特异性 T 细胞驱动的。虽然 CD4+ TH2 细胞及其产生 IL-4、IL-5 和 IL-13 的作用已得到充分证实，但导致这些产生细胞因子的 T 细胞在没有病原体入侵的情况下失去控制并引发炎症的原因尚不清楚。全基因组关联研究 (GWAS) 研究发现，调节这些 TH2 细胞产生细胞因子的途径存在缺陷。 E3 泛素连接酶 Itch 是调节小鼠和人类 TH2 产生和肺部炎症的一种途径。我们已经鉴定了一种 E3 泛素连接酶接头 Nedd4 家族相互作用蛋白 1 (Ndfip1)，它可以激活多种 E3 泛素连接酶，包括 止痒，限制 TH2 细胞分化和促炎细胞因子的产生。我们发表的数据表明，Ndfip1 可以阻止 T 细胞激活、TH2 分化以及随之而来的以杯状细胞增生和嗜酸性粒细胞增多为特征的肺部炎症。我们的初步数据揭示了 Ndfip1 如何激活 E3 泛素连接酶（如 Itch）的机制基础。这些结果可能定义激活 Itch 以及其他 Nedd4 家族成员的新范例。基于这些研究，我们设计了一种治疗性激活这些 E3 连接酶以治疗过敏性疾病的新方法。该提案的重点是测试两个相互关联的假设。我们假设 Ndfip1 解除了 Itch 的自身抑制，从而限制了 T 细胞中促炎细胞因子的产生。我们假设 Ndfip1 的治疗模拟物可用于激活泛素化级联，以限制 TH2 细胞因子的产生并减少肺部炎症。该提案中描述的实验将确定 Ndfip1 触发 Itch 激活的关键生化特征，并测试 Ndfip1 肽是否可用于限制 TH2 细胞中促炎细胞因子的产生。此外，利用定量蛋白质组学，我们将确定 Ndfip1 如何调节 TH2 细胞中促炎细胞因子产生的潜在机制。虽然该提案的重点是使用 T 细胞介导的肺部炎症小鼠模型来测试治疗潜力，但这些数据可能对设计治疗哮喘等过敏性疾病的疗法具有广泛的影响。