Myeloid Cell Signaling in Allergic Asthma

过敏性哮喘中的骨髓细胞信号转导

• 批准号: 10078643
• 负责人: Yogesh Saini
• 金额: $ 25.9万
• 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/10078643
• 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.

项目摘要 在美国，过敏性哮喘影响了2400万次哮喘患者中的一半以上。列列云（Interleukins 4（IL4）和13 （IL13）在过敏性哮喘的致病性中起着至关重要的作用。菌丝的删除 普通受体，即白介素-4受体α（IL4Rα），提供了完全保护过敏性的 哮喘表明其必不可少的作用。根据上述情况，目前阻止IL4Rα的药物是 在管理人类过敏性哮喘的临床试验下。但是，回答不是很 有希望的是，可能是由于涉及新鲜募集的IL4Rα含有细胞类型的靶向效率低下 过敏性哮喘的发病机理。这是因为IL4Rα介导的信号传导的细胞类型特异性作用 过敏性哮喘一直不清楚。识别员工IL4Rα介导的信号传导的关键细胞类型 因此，在过敏性哮喘的致病表现中可能导致更有效的治疗干预措施 在过敏性哮喘中。该提案的总体目的是描述IL4Rα信号传导的细胞特异性作用 在嗜酸性粒细胞募集和过敏性哮喘中，并确定细胞来源和分子身份 空间（气道和肺泡空域）的过敏性炎症的可溶性和囊泡结合的介质。 已经与专家建立了杰出的合作，包括哮喘专家，外泌体 蛋白质组学专家，分子病理学家，嗜酸性粒细胞生物学专家和IL4Rα生物学专家。 已经开发了包括新型转基因小鼠菌株在内的创新工具，它将允许可行和 生产投资。我们的中心假设是髓样特异性IL-4Rα信号对于 嗜酸性粒细胞的募集和过敏性哮喘的结果表现，外泌体带有 嗜酸性粒细胞募集的介体。该假设将在三个具体目标下进行检验。 AIM 1将测试 髓样IL4Rα对于嗜酸性粒细胞募集至关重要的假设；在AIM 2中，我们将检验假设 在混合过敏原挑战模型中，髓样-IL4Rα对于过敏性哮喘结局至关重要。发现 从我们的研究中将对我们对机械理解的病理生理学产生变革性的影响 过敏性哮喘。最终，我们的发现可以应用于细胞特异性治疗的发展 反对过敏性气道和其他嗜酸性疾病。