Myeloid Cell Signaling in Allergic Asthma

项目摘要 过敏性哮喘影响了美国2400万哮喘患者中的一半以上。白介素4(IL4)和13 已知白介素13在过敏性哮喘的发病机制中起重要作用。他们的生殖系缺失 共同的受体，即白介素4受体α(IL4Rα)，提供完全的保护，防止过敏 哮喘提示其不可或缺的作用。因此，阻断IL4Rα的药理学试剂目前 正在进行人类过敏性哮喘治疗的临床试验。然而，这些反应并不是很好 很有希望，可能是因为对新招募的携带IL4Rα的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IL4Rα介导的信号转导在细胞类型中的特定作用 过敏性哮喘仍不清楚。使用IL4Rα介导的信号转导的关键细胞类型的鉴定 因此，在过敏性哮喘的病因表现上可能会导致更有效的治疗干预 患有过敏性哮喘。这项提案的总体目标是描述IL4Rα信号的细胞特异性作用 在嗜酸性粒细胞募集和过敏性哮喘中的作用，并鉴定其细胞来源和分子特性 空气空间(呼吸道和肺泡空间)中的过敏性炎症的可溶性和囊泡结合性介质。 已经与专家建立了出色的合作关系，包括哮喘专家、外显体 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。 包括新型转基因小鼠品系在内的创新工具已经开发出来，将使一种可行的和 富有成效的调查。我们的中心假设是髓系特异性的IL-4Rα信号对 嗜酸性粒细胞的募集和过敏性哮喘相关结局的表现以及外周小体携带 嗜酸性粒细胞招募的中介物。这一假设将在三个具体目标下进行检验。AIM 1将测试 髓系白细胞介素4Rα是嗜酸性粒细胞募集必不可少的假说；在目标2中，我们将检验该假说 在混合变应原激发模型中，髓系白细胞介素4Rα对于过敏性哮喘的结果是必不可少的。调查结果 我们的研究将对我们从机制上理解糖尿病的病理生理学产生革命性的影响 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。 对抗过敏性呼吸道和其他嗜酸性粒细胞疾病。

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.