Cul5 and Triad1 partner to prevent T cell mediated lung inflammation and asthma

Cul5 和 Triad1 合作预防 T 细胞介导的肺部炎症和哮喘

• 批准号: 10092119
• 负责人: Paula Maria Oliver
• 金额: $ 7.89万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-29 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092119
• 关键词: Affect; Airway Disease; Allergens; Allergic Disease; American; Animals; Asthma; Binding; Biological; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cessation of life; Complex; Data; Disease; Eosinophilia; Etiology; Failure; Fibrosis; Future; Goals; Goblet Cells; Hyperplasia; Immune; Immune system; Immunoprecipitation; Inflammation; Invaded; Ligase; Lung; Lung Inflammation; Mass Spectrum Analysis; Mediating; Modeling; Mus; Parasites; Pathogenicity; Pathway interactions; Patients; Peripheral; Phenocopy; Proteomics; Pyroglyphidae; Receptor Signaling; Resources; Role; Spleen; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Therapeutic Uses; Tissues; Work; airway hyperresponsiveness; airway remodeling; base; chronic inflammatory disease; cytokine; immune activation; in vivo; innovation; lymph nodes; member; mouse model; novel; novel therapeutic intervention; pathogen; patient subsets; prevent; recruit; response; small molecule; targeted treatment; therapy design; ubiquitin ligase; ubiquitin-protein ligase

Abstract Asthma is a chronic inflammatory disease of the airways that affects 26 million Americans and results in approximately 3600 deaths per year in the US alone (1a). Asthma is a heterogeneous disease and both Th2 predominant and Th17 predominant forms have been described with different etiologies. Interestingly, it was recently determined that a subset of patients with particularly severe asthma contain T cells that make both Th2 and Th17 cytokines. However, mechanisms that prevent allergen specific T cells from becoming Th2/17 dual producers have not been described. We have identified a novel inhibitory pathway that limits the differentiation and pathogenicity of both Th2, Th9 and Th2/17 dual-producing T cells and protects against airway remodeling in mice. This pathway is controlled by the E3 ubiquitin ligase Cul5. Supporting this, we recently generated mice in which Cul5 was deleted only in T cells, and determined that Cul5 limits the numbers of Th2, Th9 and Th2/17 dual cytokine producing T cells and airway remodeling after house dust mite exposure. Specifically, we found that mice lacking Cul5 in T cells showed increased lung inflammation, eosinophilia, goblet cell hyperplasia and fibrosis, as well as AHR. Using a screen to reveal Cul5 binding partners, we identified Traid1, a RING-between- RING E3 ubiquitin ligases that was recently shown to be important for Cul5 activity. Based on these preliminary data we hypothesize that Cul5 works with Triad1 to limit the numbers of pathogenic T cells to prevent asthma. Our long term goal is to develop novel therapeutic strategies that activate the Cul5 pathway to turn T cells off in patients with asthma. However, to do this effectively we must first determine how Cul5 activity is regulated. In this proposal we will determine whether mice with a deletion of Traid1 in T cells develop a similar inflammation and airways remodeling following HDM exposure as we observed in Cul5fl/flCD4-Cre animals. This would indicate that regulating the interaction between Cul5 and Triad1 might be a good therapeutic approach.

摘要 哮喘是一种慢性气道炎症性疾病，影响2600万美国人， 仅在美国每年就有大约3600人死亡（1a）。哮喘是一种异质性疾病， 主要和Th 17主要形式已经被描述为具有不同的病因。有趣的是， 最近确定，一部分患有特别严重哮喘的患者含有T细胞， 和Th 17细胞因子。然而，防止过敏原特异性T细胞成为Th 2/17双重的机制， 生产者没有被描述。我们已经确定了一个新的抑制途径，限制分化 和Th 2、Th 9和Th 2/17双重产生T细胞的致病性，并保护气道重塑 对小鼠该途径由E3泛素连接酶Cul 5控制。为了支持这一点，我们最近培育了小鼠 其中Cul 5仅在T细胞中缺失，并且确定Cul 5限制Th 2、Th 9和Th 2/17的数量 尘螨暴露后产生双重细胞因子的T细胞与气道重塑具体来说，我们发现 在T细胞中缺乏Cul 5的小鼠表现出增加的肺部炎症、嗜酸性粒细胞增多、杯状细胞增生， 纤维化，以及AHR。使用筛选来揭示Cul 5结合伴侣，我们鉴定了Traid 1，一种介于- RING E3泛素连接酶，其最近显示对Cul 5活性重要。基于这些初步 我们假设Cul 5与Triad 1共同作用，限制致病性T细胞的数量， 哮喘我们的长期目标是开发新的治疗策略，激活Cul 5通路，将T 哮喘患者的细胞脱落然而，为了有效地做到这一点，我们必须首先确定Cul 5的活性是如何被激活的。 监管.在这项提议中，我们将确定T细胞中Traid 1缺失的小鼠是否会产生类似的 如我们在Cul 5 fl/flCD 4-Cre动物中观察到的，HDM暴露后的炎症和气道重塑。这 表明调节Cul 5和Triad 1之间的相互作用可能是一种很好的治疗方法。