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A Cul5 E3 ubiquitin ligase complex that prevents allergic asthma

预防过敏性哮喘的 Cul5 E3 泛素连接酶复合物

基本信息

批准号：
10335229
负责人：
Paula Maria Oliver
金额：
$ 57.63万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-18 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10335229
关键词：
Acute Affect Airway Disease Allergens American Antigens Asthma Binding Biochemical Bioinformatics Biological Biological Products Biology Cell Count Cell Differentiation process Cell Survival Cell physiology Cells Cellular biology Cessation of life Chronic Clustered Regularly Interspaced Short Palindromic Repeats Complement Complex Cullin Proteins Data Development Disease Eosinophilia Etiology Extrinsic asthma Fibrosis Foundations Glycine Goals Goblet Cells Hyperplasia In Vitro Individual Inflammation Inflammatory Interleukin-9 Ligase Mass Spectrum Analysis Mediating Methods Modeling Molecular Mouse Strains Mus Pathogenicity Pathology Pathway interactions Patients Predisposition Production Proteins Proteomics Pulmonary Inflammation Pyroglyphidae Reporter Role Severity of illness Signal Pathway T cell differentiation T-Cell Receptor T-Lymphocyte Th2 Cells Therapeutic Ubiquitin airway remodeling allergic airway disease asthma model asthmatic patient base chronic inflammatory disease cytokine in vivo insight mast cell novel novel therapeutic intervention prevent rational design receptor recruit response screening small molecule success targeted treatment therapy development tool transcriptome sequencing ubiquitin ligase ubiquitin-protein ligase

项目摘要

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. While Th2 cytokines are more common in patients with allergic asthma, there is variability among these patients in regards to the types of Th2 cytokines found, severity of disease, and response to currently available therapies. IL-9 producing Th9 cells are a new cytokine producing T cell that are often found in patients with allergic asthma and correlate with disease severity. However, the mechanisms that regulate Th9 differentiation and function remain largly unknown. We have identified a novel inhibitory pathway that limits the differentiation and pathogenicity of both Th2 and Th9 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 airway remodeling after asthma induction. Specifically, we found that Cul5fl/flCD4-Cre mice showed increased lung inflammation, eosinophilia, goblet cell hyperplasia and fibrosis following house dust mite exposure. T cells from Cul5fl/flCD4-Cre mice were much more likely to Th2 and Th9 cells. Using a screen to reveal Cul5 binding partners, we identified three substrate receptors that cooperate with Cul5 in T cells. Based on these preliminary data we hypothesize that Cul5 associates with one or more of these substrate receptors to ubiquitylate substrates and thus limits the differentiation of Th2 and Th9 cells and prevents asthma. Based on our preliminary data, our long term goal is to develop novel therapeutic strategies that activate the Cul5 pathway to turn Th2 and Th9 cells off in patients with asthma. However, to do this effectively we must first determine 1) how Cul5 regulates T cell biology, 2) determine how interacting partners aid Cul5 function, and 3) delineate how, on a mechanistic level, Cul5 complexes limit T cell differentiation and pathogenicity (i.e identify substrates). In this proposal we will determine key aspects of how Cul5 restricts T cell differentiation and function, thus revealing the signaling pathways that allow Th9 cells to develop and drive asthma. Additionally, we will identify regulatory mechanisms that promote the activation and function of Cul5. This information will provide crucial information needed as we begin to develop therapies to target Cul5 to reduce the differentiation of Th2 and Th9 cells in allergic asthma.

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。Th 2细胞因子在过敏性哮喘患者中更常见，在这些患者中，发现的Th 2细胞因子的类型、疾病的严重程度和对目前可用疗法的反应。IL-9产生 Th 9细胞是一种新的产生细胞因子的T细胞，经常在过敏性哮喘患者中发现，疾病的严重程度。然而，调节Th 9分化和功能的机制仍然存在很大的差异。未知我们已经确定了一种新的抑制途径，限制了两者的分化和致病性。 Th 2和Th 9细胞，并保护小鼠气道重塑。该途径由E3泛素控制连接酶Cul 5.支持这一点，我们最近产生了小鼠，其中Cul 5仅在T细胞中被删除，确定Cul 5限制哮喘诱导后的气道重塑。具体来说，我们发现Cul 5 fl/flCD 4-Cre 小鼠在接触室内灰尘后，肺部炎症、嗜酸性粒细胞增多、杯状细胞增生和纤维化增加螨暴露。来自Cul 5 fl/flCD 4-Cre小鼠的T细胞更可能是Th 2和Th 9细胞。使用屏幕来为了揭示Cul 5结合伴侣，我们鉴定了在T细胞中与Cul 5合作的三种底物受体。基于根据这些初步数据，我们假设Cul 5与这些底物中的一种或多种结合，受体的泛素化底物，从而限制了Th 2和Th 9细胞的分化，哮喘根据我们的初步数据，我们的长期目标是开发新的治疗策略， Cul 5通路关闭哮喘患者的Th 2和Th 9细胞。然而，为了有效地做到这一点，我们必须首先确定1）Cul 5如何调节T细胞生物学，2）确定相互作用伴侣如何辅助Cul 5功能，和 3)描述Cul 5复合物如何在机制水平上限制T细胞分化和致病性（即鉴定基质）。在这项提案中，我们将确定Cul 5如何限制T细胞分化和功能的关键方面，从而揭示了允许Th 9细胞发展和驱动哮喘的信号通路。此外，我们将鉴定促进Cul 5的激活和功能的调节机制。这些信息将提供当我们开始开发靶向Cul 5的疗法以减少Th 2分化时，和Th 9细胞在过敏性哮喘中的作用。