Scientific innovation for personalized severe asthma management

个性化重症哮喘管理的科学创新

• 批准号: 10269966
• 负责人: Benjamin Gaston
• 金额: $ 242.07万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10269966
• 关键词: Address; Adrenergic Agents; Affect; Alkalinization; Androgen Receptor; Androgens; Asthma; Basic Science; Biological; Biology; Biostatistics Core; Bronchoscopy; Buffers; Cell Culture Techniques; Cell physiology; Cells; Cellular biology; Clinical Trials; Coenzyme A; Data; Data Analyses; Enzymes; Epithelial Cells; Functional disorder; Gene Expression; Goals; Health Care Costs; Human; IL4 gene; In Vitro; Indiana; Inflammation; Inhalation; Institution; Interleukin-17; Intervention; Lung; Mediating; Monitor; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Obstructive Lung Diseases; Oxidoreductase; Pathway interactions; Patients; Program Research Project Grants; Receptor Signaling; Regulation; Research Project Grants; Role; S-Nitrosoglutathione; S-Nitrosothiols; Safety; Science; Signal Transduction; Specimen; Translating; United States; Universities; airway epithelium; airway inflammation; beta-2 Adrenergic Receptors; cost; data dissemination; dehydroepiandrosterone; disabling disease; in vivo; innovation; mortality; novel; novel strategies; novel therapeutics; personalized medicine; programs; receptor expression; synergism; therapeutic development

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.

项目摘要/摘要 我们的总体目标是表征最近确定的机制的细胞生物学和生理学 严重的哮喘。严重的哮喘是一种残疾阻塞性肺疾病，占多数 与哮喘有关的发病率和死亡率；它的年度医疗保健费用超过100亿美元 仅在美国。严重的哮喘一直是我们治疗发展工作的一个重点。 我们发现并研究了与严重哮喘有关的三种新型机制。这些包括在 严重的哮喘：1）β2肾上腺素受体通过S-硝基化调节； 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通过新颖的个性化疗法来治疗 这将在每个项目的第三个目标中以完整的方式进行研究。三个协同建议 提出了项目：严重哮喘的项目1，S-亚硝基化信号传导；项目2，Airway pH调节 严重的哮喘；和项目3，严重哮喘中的雄激素信号传导。请注意，大量 科学和大多数拟议的核心目前都纳入了NHLBI赞助的翻译P01 在我们的两个机构，印第安纳大学和案例西部储备大学。但是，NHLBI不是 计划更新其翻译P01计划。然而，这对当前建议意味着 科学界面以及核心目前正在运行；而且它们在任何一个机构都没有重复。 我们建议在当前建议中继续这些核心功能。这三个项目有科学 协同作用。例如，有害的非硝基化（项目1）都被气道碱化反转（项目 2）和通过气道上皮雄激素治疗（项目3）。白介素17，减少气道上皮S- 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）。白介素4基因表达似乎受到人类气道碱化的抑制（项目 2）和通过雄激素受体信号传导（项目3）。这些和相关的相互作用将详细研究。这 程序还具有强大的操作协同作用。每个项目都将使用每个核心。尤其是每个 将使用研究支气管镜检查和生物测量核心的数据和标本以及严重的 哮喘临床试验核心；每个人都将使用来自原发性人类气道细胞培养核心的细胞；每个都会依靠 大量的肺生物统计学核心用于数据分析；所有项目和核心将由 行政核心。请注意，行政核心还将为所有数据传播提供帮助， 与演讲者和咨询委员会。这三个项目都无法支持这些核心 作为独立R01的功能。在该计划的结束时，我们预计已经使用了我们的基本 科学创新至少开发三种新型方法来管理严重的哮喘。