Asthma Inflammation Research

摘要-- 超过2500万美国人患有哮喘，近一半的哮喘没有得到控制。 标准治疗是有限的，阶梯式护理方法统一适用于所有患者， 哮喘的潜在机制。我们的哮喘炎症研究[空气]计划旨在揭示 哮喘的基本机制，并确定这些途径的生物标志物， 哮喘的内在型，以便在精确的医疗护理方法中进行靶向治疗。在第一周期中， TPPG，我们发现了气道炎症和高反应性的新机制。在周期II中，我们应用 精确靶向支气管扩张（项目3）和炎症（项目4）途径的基本发现 1和2）。基于氧化代谢机制导致哮喘的发现，项目1 研究饮食是否可以调节炎症反应、基因表达和气道反应性。 代谢内型将被阐明，嗜酸性粒细胞活化的特异性生物标志物溴酪氨酸 （BrTyr）在哮喘控制和基于生物的哮喘治疗中进行了测试。项目2已确定T-Helper 17 [TH 17]途径在严重哮喘的起源。在周期II中，项目2确定TH 17细胞因子 驱动病理性炎症，并使用这些信息来开发这种内型的血清生物标志物， IL-17 A小分子抑制剂和肽模拟物用于治疗哮喘。项目3显示，高 哮喘气道中的一氧化氮（NO）和氧化剂水平损害可溶性鸟苷酸环化酶（sGC）， 它对NO不敏感，并减少NO-sGC途径在支气管扩张中的作用。在第二周期，项目3 开发支气管扩张剂药物反应谱，以鉴定sGC内型，并检测sGC激活剂， 哮喘临床前模型中的刺激物，以支持sGC药物作为支气管扩张剂的新适应症。的 项目受益于模型系统和核心效率，包括新的技术开发和 商业化核心B，以及核心C中的哮喘和气流成像的创新小鼠模型。 与制药和生物技术、营养、健康和保健公司建立合作伙伴关系， 利用总部位于奥克兰的NHLBI国家加速创新中心（NCAI-CC）和NSF Cleveland Clinic的Innovations Corps确保我们的发现将在未来5年内实施。 总之，该计划为个性化哮喘的有效进展提供了无与伦比的机会 为患者提供医疗保健产品。

ABSTRACT – OVERALL PROGRAM More than 25 million Americans suffer from asthma, and nearly half do not have their asthma under control. Standard treatment is limited, and a stepped care approach is applied uniformly to all patients regardless of the underlying mechanisms of asthma. Our Asthma Inflammation Research [AIR] Program aims to uncover fundamental mechanisms of asthma and identify biomarkers of those pathways that will define mechanistic endotypes of asthma in order to target therapies in a precision medicine approach of care. In Cycle I of the TPPG, we uncovered new mechanisms of airway inflammation and hyper-reactivity. In Cycle II, we apply the fundamental discoveries to precisely target pathways for bronchodilation (Project 3) and inflammation (Projects 1 and 2). Based on findings that oxidative metabolism mechanistically contributes to asthma, Project 1 investigates whether diet can modulate inflammatory responses, gene expression, and airway reactivity. Metabolic endotypes will be elucidated, and a specific biomarker of eosinophil activation, bromotytrosine (BrTyr) is tested in asthma control and biologic-based therapies of asthma. Project 2 has identified T-Helper 17 [TH17] pathways in origins of severe asthma. In Cycle II, Project 2 determines if, and how, TH17 cytokines drive pathologic inflammation, and uses the information to develop serum biomarkers of this endotype, and small molecule inhibitors and peptidomimetics of IL-17A for treatment of asthma. Project 3 shows that high levels of nitric oxide (NO) and oxidants in asthmatic airways damage soluble guanylate cyclase (sGC), making it NO-insensitive and diminishing the NO-sGC pathway from acting in bronchodilation. In Cycle II, Project 3 develops bronchodilator drug response profiling to identify sGC endotypes, and tests sGC activators and stimulators in asthma preclinical models to support a new indication for sGC drugs as bronchodilators. The projects benefit from model systems and efficiencies of cores, including a new Technology Development and Commercialization Core B, and innovative murine models of asthma and airflow imaging in Core C. Partnerships with Pharmaceutical & Biotechnology, Nutrition, Health & Wellness companies, and strategic leveraging of Cleveland-based NHLBI National Centers for Accelerating Innovation (NCAI-CC) and the NSF Innovations Corps at Cleveland Clinic ensure that our discoveries will be implemented over the next 5 years. Altogether, the program provides an unparalleled opportunity for efficient progression of personalized asthma care products to the marketplace for patients.