Myeloid Cell Signaling in Allergic Asthma

过敏性哮喘中的骨髓细胞信号转导

• 批准号: 10341066
• 负责人: Yogesh Saini
• 金额: $ 22.09万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-02 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341066
• 关键词: Ablation; Affect; Allergens; Allergic; Allergic inflammation; Alveolar; Asthma; Biological Assay; Biology; Cells; Clinical Trials; Collaborations; Complex; Data; Development; Disease; Eosinophilia; Epithelial; Extrinsic asthma; Fibrosis; Functional disorder; Gene Expression Profiling; Germ Lines; Human; IL4 gene; Inflammation Mediators; Interleukin 4 Receptor; Interleukin-13; Interleukin-4; Investigation; Knock-out; Lead; Lung; Mediating; Mediator of activation protein; Metaplastic Cell; Modeling; Molecular; Mouse Strains; Mucous body substance; Mus; Myelogenous; Myeloid Cells; Outcome; Pathogenesis; Pathogenicity; Pathologist; Pharmaceutical Preparations; Pharmacology; Play; Production; Proteomics; Role; Signal Transduction; Source; Specialist; Stress; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; United States; Vesicle; airway hyperresponsiveness; asthmatic; cell preparation; cell type; cytokine; eosinophil; exosome; genetic signature; innovation; mouse model; novel; preclinical trial; receptor; recruit; response; targeted treatment; therapeutically effective; tool

Project Summary Allergic asthma affects over half of the 24 million asthmatics in the United States. Interleukins 4 (IL4) and 13 (IL13) are known to play an essential role in the pathogenicity of allergic asthma. Germ-line deletion of their common receptor, i.e. Interleukin-4 receptor alpha (IL4Rα), provides complete protection against allergic asthma suggesting its indispensable role. Accordingly, pharmacological agents blocking IL4Rα are currently under clinical trials for management of human allergic asthma. The responses are, however, not very promising, perhaps due to the inefficient targeting of a freshly recruited IL4Rα-bearing cell-type involved in the pathogenesis of allergic asthma. This is because the cell-type specific role of IL4Rα-mediated signaling in allergic asthma has remained unclear. Identification of a key cell-type that employs IL4Rα-mediated signaling in pathogenic manifestation of allergic asthma may, therefore, lead to a more effective therapeutic intervention in allergic asthma. The overall objective of this proposal is to delineate the cell-specific role of IL4Rα signaling in eosinophil recruitment and allergic asthma and to identify the cellular source and molecular identity of soluble and vesicle-bound mediators of allergic inflammation in airspaces (airway and alveolar airspaces). Outstanding collaborations have been established with experts, including an asthma specialist, an exosomes proteomics specialist, a molecular pathologist, an eosinophil biology expert, and an IL4Rα biology expert. Innovative tools, including novel transgenic mouse strains, have been developed that will allow a feasible and productive investigation. Our central hypothesis is that myeloid-specific IL-4Rα signaling is essential for recruitment of eosinophils and manifestation of allergic asthma-relevant outcomes and that exosomes carry the mediators of eosinophil recruitment. This hypothesis will be tested under three specific aims. Aim 1 will Test the hypothesis that myeloid IL4Rα is essential for eosinophil recruitment; in Aim 2 we will Test the hypothesis that myeloid-IL4Rα is essential for allergic asthma outcomes in a mixed allergen challenge model. The findings from our studies will have a transformative impact on our mechanistic understanding of the pathophysiology of allergic asthma. Eventually, our findings may be applied towards the development of cell-specific therapeutics against allergic airway and other eosinophilic disorders.

项目概要 美国 2400 万哮喘患者中有一半以上患有过敏性哮喘。白细胞介素 4 (IL4) 和 13 已知 (IL13) 在过敏性哮喘的致病性中发挥重要作用。种系缺失 共同受体，即白细胞介素 4 受体 α (IL4Rα)，可提供全面的过敏保护 哮喘提示其不可缺少的作用。因此，目前阻断IL4Rα的药物 正在进行治疗人类过敏性哮喘的临床试验。但得到的回应却并不十分 有希望，可能是由于新招募的 IL4Rα 承载细胞类型的靶向效率低下，该细胞类型参与了 过敏性哮喘的发病机制。这是因为 IL4Rα 介导的信号传导的细胞类型特异性作用 过敏性哮喘尚不清楚。鉴定采用 IL4Rα 介导的信号传导的关键细胞类型 因此，过敏性哮喘的致病表现可能会导致更有效的治疗干预 在过敏性哮喘中。该提案的总体目标是描述 IL4Rα 信号传导的细胞特异性作用 嗜酸性粒细胞募集和过敏性哮喘，并鉴定其细胞来源和分子特性 气腔（气道和肺泡气腔）中过敏性炎症的可溶性和囊泡结合介质。 与专家建立了杰出的合作，包括哮喘专家、外泌体专家 蛋白质组学专家、分子病理学家、嗜酸性粒细胞生物学专家、IL4Rα生物学专家。 已经开发出创新工具，包括新型转基因小鼠品系，这将允许可行且可行的方法 富有成效的调查。我们的中心假设是骨髓特异性 IL-4Rα 信号传导对于 嗜酸性粒细胞的募集和过敏性哮喘相关结果的表现以及外泌体携带 嗜酸性粒细胞募集的介质。该假设将在三个具体目标下进行检验。目标 1 将测试 骨髓 IL4Rα 对于嗜酸性粒细胞募集至关重要的假设；在目标 2 中，我们将检验假设 在混合过敏原激发模型中，骨髓-IL4Rα 对于过敏性哮喘的结果至关重要。研究结果 我们的研究将对我们对病理生理学的机械理解产生变革性影响 过敏性哮喘。最终，我们的发现可能应用于细胞特异性疗法的开发 对抗过敏性气道和其他嗜酸性粒细胞疾病。