Asthma Inflammation Research

抽象-总体程序 超过2500万美国人患有哮喘，近一半的人哮喘得不到控制。 标准治疗是有限的，分级护理方法统一应用于所有患者，而不考虑 哮喘的潜在机制。我们的哮喘炎症研究[AIR]项目旨在揭示 哮喘的基本机制，并确定那些将定义机制的途径的生物标记物 为了对哮喘内型进行靶向治疗，采用精准医学的方法进行护理。在第一个周期中 我们发现了呼吸道炎症和高反应性的新机制。在第二个周期中，我们应用 精确定位支气管扩张途径(项目3)和炎症途径(项目3)的基本发现 1和2)。基于氧化代谢对哮喘的机械性贡献的发现，项目1 研究饮食是否可以调节炎症反应、基因表达和呼吸道反应性。 将阐明代谢内型，以及嗜酸性粒细胞激活的特定生物标记物溴酪氨酸 (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 [Th17]严重哮喘发生的途径。在第二周期中，项目2决定是否以及如何产生TH17细胞因子 驱动病理性炎症，并利用这些信息开发这种内型的血清生物标记物，以及 用于哮喘治疗的IL-17A的小分子抑制剂和肽类药物。项目3显示，高 哮喘呼吸道中一氧化氮(NO)和氧化剂的水平损害了可溶性鸟苷环化酶(SGC)，使 它对NO不敏感，减少了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确定sGC内型，并测试sGC激活剂和 哮喘临床前模型中的刺激物支持sGC药物作为支气管扩张剂的新适应症。这个 项目受益于模型系统和核心的效率，包括新的技术开发和 将核心B商业化，并在核心C中创新哮喘小鼠模型和气流成像。 与制药和生物技术、营养、健康和健康公司的合作伙伴关系，以及战略 利用位于克利夫兰的NHLBI国家加速创新中心(NCAI-CC)和NSF 克利夫兰诊所的创新团队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 护理产品推向市场，为患者服务。

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.