Scientific innovation for personalized severe asthma management

项目概要/摘要 我们的总体目标是表征最近确定的潜在机制的细胞生物学和生理学 严重哮喘严重哮喘是一种致残性阻塞性肺病， 与哮喘相关的发病率和死亡率;每年的医疗保健费用超过100亿美元 仅在美国。重度哮喘一直是我们治疗开发工作的重点。 我们发现并研究了三种与严重哮喘相关的新机制。其中包括在 重度哮喘：1）S-亚硝基化对β2肾上腺素能受体的调节; 2）气道酸化; 3）雄激素 信号这三种机制中的每一种都有可能用新的个性化疗法来治疗 这将在每个项目的第三个目标中以互补的方式进行研究。三个协同建议 提出的项目：项目1，严重哮喘中的S-亚硝基化信号;项目2， 严重哮喘;以及项目3，严重哮喘中的雄激素信号传导。请注意，大量的 科学，以及大多数提议的核心，目前被纳入NHLBI赞助的翻译P01 在我们的两个机构，印第安纳州大学和凯斯西储大学。然而，NHLBI不是 计划更新其翻译P01倡议。然而，这对目前的提案意味着， 科学接口以及核心数据库目前正在运行;两个机构都没有重复。 我们建议在目前的提案中继续这些核心职能。三个项目具有科学性 协同作用。例如，有害的去亚硝基化（项目1）被气道碱化（项目2）逆转， 2)和气道上皮雄激素治疗（项目3）。白细胞介素17，减少气道上皮S- 亚硝基硫醇信号传导（项目1）被气道碱化（项目2）和雄激素受体信号传导抑制 （项目3）。白细胞介素4基因表达似乎受到人气道碱化的抑制（项目 2)和雄激素受体信号传导（项目3）。将详细研究这些相互作用和相关的相互作用。的 该计划还具有强大的业务协同作用。每个项目都将使用每个核心。特别是，每个 将使用来自研究支气管镜检查和生物标本核心和严重支气管炎的数据和标本。 哮喘临床试验核心;每项试验将使用来自原代人气道细胞培养核心的细胞;每项试验将依赖 肺生物统计学核心数据分析的重要性;所有项目和核心将由 行政核心。请注意，行政核心还将协助所有项目传播数据， 演讲者和咨询委员会。这三个项目都无法支持这些核心项目。 作为独立的R 01。在本计划结束时，我们预计已经使用了我们的基本 科学创新，以开发至少三种新的方法来管理严重哮喘。

PROJECT SUMMARY/ABSTRACT Our overall goal is to characterize the cell biology and physiology of recently identified mechanisms underlying severe asthma. Severe asthma is a disabling obstructive lung disease that accounts for the majority of the morbidity and mortality associated with asthma; it accounts for annual healthcare costs in excess of $10 billion in the United States alone. Severe asthma has been a particular focus of our therapeutic development efforts. We have discovered and studied three novel mechanisms relevant to severe asthma. These include the role in severe asthma of: 1) β2 adrenergic receptor regulation by S-nitrosylation; 2) airway acidification; and 3) androgen signaling. Each of these three mechanisms has the potential to be treated with novel, personalized therapies that will be studied in a complementary fashion in the third Aim of each Project. Three synergistic proposed Projects are proposed: Project 1, S-nitrosylation signaling in severe asthma; Project 2, airway pH regulation in severe asthma; and Project 3, androgen signaling in severe asthma. Note that a substantial amount of the science, and most of the proposed Cores, are currently incorporated in an NHLBI –sponsored Translational P01 at our two institutions, Indiana University and Case Western Reserve University. However, the NHLBI is not planning to renew its Translational P01 initiative. What this means for the current proposal, however, is that the scientific interface, as well as the Cores, are currently operational; and they are not duplicated at either institution. We propose to continue these Core functions in the current proposal. The three Projects have scientific synergy. For example, detrimental denitrosylation (Project 1) is reversed both by airway alkalinization (Project 2) and by airway epithelial androgen treatment (Project 3). Interleukin 17, which decreases airway epithelial S- nitrosothiol signaling (Project 1) is inhibited by airway alkalinization (Project 2) and androgen receptor signaling (Project 3). Interleukin 4 gene expression appears to be inhibited both by human airway alkalinization (Project 2) and by androgen receptor signaling (Project 3). These and related interactions will be studied in detail. The Program also has robust operational synergy. Each Project will make use of each core. In particular, each will use data and specimens from the Research Bronchoscopy and Biospecimens Core and from the Severe Asthma Clinical Trials Core; each will use cells from the Primary Human Airway Cell Culture Core; each will rely heavily on the Pulmonary Biostatistics Core for data analysis; and all projects and cores will be coordinated by an Administrative Core. Note that the Administrative Core will also assist all Projects with data dissemination, with speakers and with advisory boards. None of the three Projects would be able to support these Core functionalities as an independent R01. At the conclusion of this Program, we anticipate having used our basic science innovations to develop at least three novel approaches to managing severe asthma.