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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：
10166765
负责人：
Paula Maria Oliver
金额：
$ 57.91万
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/10166765
关键词：
Acute Affect Airway Disease Allergens American Antigens Asthma Binding Biochemical Bioinformatics Biological 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 Lung Inflammation Mass Spectrum Analysis Mediating Methods Modeling Molecular Mouse Strains Mus Pathogenicity Pathology Pathway interactions Patients Predisposition Production Proteins Proteomics 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 receptor recruit response screening small molecule success targeted treatment therapy design 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.

哮喘是一种呼吸道的慢性炎症性疾病，影响着2600万美国人，导致