Myeloid Cell Signaling in Allergic Asthma

过敏性哮喘中的骨髓细胞信号转导

基本信息

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
项目类别：
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

项目摘要

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.

项目概要美国有 2400 万哮喘患者，其中一半以上患有白介素 4 (IL4) 和 13。已知 (IL13) 在过敏性哮喘的种系缺失中发挥重要作用。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因此，目前阻断 IL4Rα 的药物已成为哮喘治疗中不可或缺的作用。然而，治疗人类过敏性哮喘的临床试验效果并不理想。有前途，可能是由于新招募的 IL4Rα 承载细胞类型的靶向效率低下，该细胞类型参与了这是因为IL4Rα介导的信号传导在细胞类型中具有特异性作用。过敏性哮喘中使用 IL4Rα 介导的信号传导的关键细胞类型的鉴定仍不清楚。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的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，这将使得可行且可行的方法成为可能。我们的中心假设是骨髓特异性 IL-4Rα 信号传导对于这一过程至关重要。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该假设将在三个具体目标下进行检验。骨髓 IL4Rα 对于嗜酸性粒细胞募集至关重要的假设，我们将在目标 2 中检验该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。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最终，我们的发现可以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。