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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.

项目总结