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.

项目摘要 美国2400万哮喘患者中有一半以上受到过敏性哮喘的影响。白细胞介素4（IL 4）和13 已知IL-13在过敏性哮喘的致病性中起重要作用。他们的生殖系缺失 一种常见的受体，即白细胞介素-4受体α（IL-4 R α），可提供完全的保护， 哮喘提示其不可或缺的作用。因此，阻断IL 4 R α的药理学药物目前是 用于治疗人类过敏性哮喘的临床试验然而，反应并不十分 这可能是由于对新募集的IL 4 R α携带细胞类型的靶向效率低下， 过敏性哮喘的发病机制。这是因为IL 4 R α介导的信号传导在细胞类型特异性中的作用。 过敏性哮喘仍不清楚。鉴定使用IL 4 R α介导的信号传导的关键细胞类型 因此，在过敏性哮喘致病表现中， 过敏性哮喘该提案的总体目标是描述IL 4 R α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，并确定细胞来源和分子身份， 气道（气道和肺泡）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关系，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和IL 4 R α生物学专家。 创新的工具，包括新的转基因小鼠品系，已经开发出来，这将允许一个可行的， 生产性调查。我们的中心假设是，骨髓特异性IL-4 R α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， 嗜酸性粒细胞募集的介质。这一假设将在三个具体目标下进行检验。目标1将测试 髓系IL 4 R α对嗜酸性粒细胞募集至关重要的假设;在目标2中，我们将检验这一假设 在混合过敏原激发模型中，髓系IL 4 R α对过敏性哮喘的结局至关重要。这些发现 我们的研究将对我们对疾病病理生理学的机械理解产生变革性的影响。 过敏性哮喘最终，我们的发现可能会应用于细胞特异性治疗的发展 对抗过敏性气道和其他嗜酸性粒细胞疾病。