Role of Aiolos in eosinophilic asthma

Aiolos 在嗜酸性粒细胞性哮喘中的作用

• 批准号: 10092082
• 负责人: Marc E. Rothenberg
• 金额: $ 39万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-16 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092082
• 关键词: 17q21; Allergens; Applications Grants; Asthma; Binding; Blood; Blood Circulation; CC chemokine receptor 3; CCL11 gene; Cells; Childhood Asthma; Clinical; Clinical Treatment; Clinical Trials; Consensus; Cytoplasmic Granules; Development; Disease; Dose; Eosinophilia; Eotaxin; Event; Experimental Models; FDA approved; Feedback; Gene Expression; Genes; High Prevalence; Hospitalization; Human; Impairment; In Vitro; Inflammation; Inflammatory; Interleukin-5; Introns; Lead; Leukocytes; Ligands; Lung; Mediating; Mus; Mutation; Pathogenesis; Pathology; Pathway interactions; Patient Selection; Patients; Phenotype; Prevalence; Process; Proteins; Regulation; Regulatory Pathway; Reporting; Residual state; Risk; Role; Selection for Treatments; Severity of illness; Single Nucleotide Polymorphism; System; Testing; Therapeutic; Tissues; Transcriptional Activation; Variant; allergic airway inflammation; asthma exacerbation; asthma model; base; chemokine; chemokine receptor; cytokine; cytotoxic; eosinophil; eosinophilic asthma; eosinophilic inflammation; genetic signature; genome-wide; human disease; improved; in vivo; interleukin-5 receptor; lipid mediator; migration; novel therapeutics; overexpression; patient subsets; persistent symptom; progenitor; promoter; pulmonary function; recruit; response; targeted treatment; therapy design; trafficking; transcription factor; transcriptome; translational study

Project Summary Recruitment of eosinophils (Eos) from the bloodstream into tissues can occur under a variety of conditions and lead to the release of preformed and newly synthesized products, including cytokines, chemokines, lipid mediators and cytotoxic granule proteins, which can initiate and quickly escalate local inflammatory and remodeling responses. Notably, eosinophil-targeted therapy has been very effective in clinical trials at reducing mature eosinophils in the blood. However, tissue eosinophilia is only partially suppressed and likely results from accessory pathways that continue to promote Eos recruitment and survival. The residual tissue eosinophilia contributes to persistent symptoms and increased risk for tissue damage in patients with Eos-mediated diseases. Thus, new therapies designed with an improved understanding of the mechanism of tissue eosinophilia are needed and likely to have a significant clinical impact. Our preliminary studies implicate Aiolos as a potential regulator of Eos accumulation in eosinophilic asthma as Aiolos-deficiency results in impaired responses to CCR3 ligands and to IL-5, a key cytokine in the pathogenesis of eosinophilic asthma. The central hypothesis of this proposal is that Aiolos controls airway eosinophilia in asthma by two processes, 1) positive regulation of Ccr3 expression by direct transcriptional activation, and 2) a positive feedback loop involving Aiolos, Il5ra, and IL-5. In Aim 1, we will identify the Aiolos-dependent transcriptome in Eos and delineate the mechanism for Aiolos-dependent expression of CCR3. We will also determine the consequence of Aiolos deficiency on Eos-mediated tissue pathology in experimental asthma. In Aim 2, we will determine the mechanism for Aiolos-mediated regulation of IL-5-responsiveness by evaluating the consequence of Aiolos deficiency, haploinsufficiency and overexpression on stage-specific responses by EoPs, eosinophil precursors (preEos) and mature Eos to IL-5. We will also dissect the relationship between Aiolos expression, Il5ra expression and IL-5 stimulation during Eos development in the setting of experimental asthma. Finally, in Aim 3, we will determine the relationship between expression levels of Aiolos in human Eos and 1) a specific Eos gene signature, 2) functional response of Eos to IL-5 and CCL11, and 3) asthma disease severity and Eos phenotype. The high prevalence of eosinophilic inflammation in pediatric asthma and the recent FDA approval of IL-5-targeted therapy for eosinophilic asthma highlight the significance of this application which focuses on delineating the mechanistic relationship between Aiolos expression in Eos, Eos recruitment into the inflamed lung, and IL-5 responsiveness of Eos. Our proposed mechanistic studies using both mouse and human cell systems (Aims 1 and 2) supported by translational studies with Eos from patients with eosinophilic asthma (Aim 3) will provide compelling evidence to support our central hypothesis. The immediate significance of our study is its potential to uncover a dose-dependent relationship between Aiolos expression in Eos and response to IL-5 which would provide rationale for therapy selection for patients based on the Eos phenotype (e.g. Aiolos expression level).

项目概要 嗜酸性粒细胞 (Eos) 从血流募集到组织中可以在多种条件下发生 并导致预制和新合成产物的释放，包括细胞因子、趋化因子、 脂质介质和细胞毒性颗粒蛋白，可以启动并快速升级局部 炎症和重塑反应。值得注意的是，嗜酸性粒细胞靶向治疗在以下方面非常有效： 减少血液中成熟嗜酸性粒细胞的临床试验。然而，组织嗜酸性粒细胞增多仅部分 抑制并可能是由继续促进 Eos 募集和的辅助途径引起的 生存。残留的组织嗜酸性粒细胞增多会导致持续症状并增加组织感染的风险 Eos 介导的疾病患者的损伤。因此，设计出改进的新疗法 需要了解组织嗜酸性粒细胞增多的机制，并且可能具有重要的临床意义 影响。我们的初步研究表明 Aiolos 是嗜酸性粒细胞中 Eos 积累的潜在调节剂。 哮喘，因为 Aiolos 缺乏会导致对 CCR3 配体和 IL-5（哮喘中的关键细胞因子）的反应受损 嗜酸性粒细胞性哮喘的发病机制。该提案的中心假设是艾俄洛斯控制气道 哮喘中嗜酸性粒细胞增多的机制有两个：1）直接调节 Ccr3 的表达 转录激活，2) 涉及 Aiolos、Il5ra 和 IL-5 的正反馈循环。在目标 1 中，我们将 鉴定 Eos 中 Aiolos 依赖性转录组并描述 Aiolos 依赖性机制 CCR3 的表达。我们还将确定 Aiolos 缺陷对 Eos 介导的组织的影响 实验性哮喘的病理学。在目标 2 中，我们将确定 Aiolos 介导的机制 通过评估 Aiolos 缺陷、单倍体不足和 EoP、嗜酸性粒细胞前体 (preEos) 和成熟 Eos 对 IL-5 的阶段特异性反应过度表达。我们 还将剖析Eos期间Aiolos表达、Il5ra表达和IL-5刺激之间的关系 实验性哮喘环境中的发展。最后，在目标 3 中，我们将确定之间的关系 Aiolos 在人类 Eos 中的表达水平以及 1) 特定的 Eos 基因特征，2) Eos 对 IL-5 和 CCL11，以及 3) 哮喘疾病严重程度和 Eos 表型。嗜酸性粒细胞增多症的患病率很高 小儿哮喘炎症以及 FDA 最近批准的 IL-5 靶向治疗嗜酸性粒细胞性哮喘 强调该应用程序的重要性，其重点是描绘之间的机械关系 Eos 中的 Aiolos 表达、Eos 募集到发炎的肺部以及 Eos 的 IL-5 反应性。我们提出的 在转化研究的支持下，使用小鼠和人类细胞系统（目标 1 和 2）进行机制研究 来自嗜酸性粒细胞性哮喘患者的 Eos（目标 3）将提供令人信服的证据来支持我们的中心研究 假设。我们研究的直接意义在于它有可能揭示剂量依赖性关系 Eos 中 Aiolos 的表达与对 IL-5 的反应之间的关系，这将为治疗选择提供依据 基于 Eos 表型的患者（例如 Aiolos 表达水平）。