Scientific innovation for personalized severe asthma management

个性化重症哮喘管理的科学创新

• 批准号: 10457990
• 负责人: Benjamin Gaston
• 金额: $ 240.94万
• 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/10457990
• 关键词: Address; Adrenergic Agents; Affect; Alkalinization; Androgen Receptor; Androgens; Asthma; Basic Science; Biological Products; 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，占大多数 与哮喘相关的发病率和死亡率；每年的医疗费用超过 100 亿美元 仅在美国。严重哮喘一直是我们治疗开发工作的特别重点。 我们发现并研究了三种与严重哮喘相关的新机制。这些角色包括 严重哮喘：1）β2肾上腺素受体通过S-亚硝基化调节； 2）气道酸化； 3) 雄激素 发信号。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 将在每个项目的第三个目标中以补充方式进行研究。三大协同建议 拟议项目： 项目1，严重哮喘中的S-亚硝基化信号传导；项目2、气道pH值调节 严重哮喘；项目3，严重哮喘中的雄激素信号传导。请注意，大量的 科学以及大多数拟议的核心目前已纳入 NHLBI 赞助的转化 P01 在我们的两所院校，印第安纳大学和凯斯西储大学。然而，NHLBI 并不 计划更新其 Translational P01 计划。然而，这对于当前提案意味着 科学接口以及核心目前正在运行；并且它们在任何一个机构都不会重复。 我们建议在当前提案中继续这些核心功能。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）可以通过气道碱化（项目 2）并通过气道上皮雄激素治疗（项目3）。白细胞介素 17，可降低气道上皮 S- 亚硝基硫醇信号传导（项目 1）受到气道碱化（项目 2）和雄激素受体信号传导的抑制 （项目3）。白细胞介素 4 基因表达似乎受到人类气道碱化的抑制（Project 2) 和雄激素受体信号传导（项目 3）。这些以及相关的相互作用将被详细研究。这 该计划还具有强大的运营协同作用。每个项目都会利用每个核心。特别是，每个 将使用来自研究支气管镜检查和生物样本核心以及来自严重 哮喘临床试验核心；每个都将使用来自原代人类气道细胞培养核心的细胞；每个都会依赖 重点关注肺生物统计学核心的数据分析；所有项目和核心都将由 行政核心。请注意，管理核心还将协助所有项目进行数据传播， 与演讲者和顾问委员会。这三个项目都无法支持这些核心 作为独立的R01的功能。在本计划结束时，我们预计已经使用了我们的基本 科学创新开发至少三种治疗严重哮喘的新方法。