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.

项目摘要/摘要 我们的总体目标是描述最近发现的潜在机制的细胞生物学和生理学特征。 严重的哮喘。严重哮喘是一种致残性阻塞性肺疾病，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努力的一个特别重点。 我们发现并研究了三种与严重哮喘相关的新机制。其中包括在 重症哮喘：1)S-亚硝化对β-2肾上腺素能受体的调节；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用新的、个性化的疗法来治疗 将在每个项目的第三个目标中以互补的方式研究这一点。提出三个协同 提出的项目：项目1，S-重症哮喘中的硝酸化信号；项目2，呼吸道pH调节 严重哮喘；以及项目3，严重哮喘中的雄激素信号。请注意，相当数量的 科学，以及大多数拟议的核心，目前被纳入NHLBI赞助的翻译P01 在我们的两个机构，印第安纳大学和凯斯西储大学。然而，NHLBI并非如此 计划更新其翻译P01计划。然而，这对目前的提案意味着， 科学接口以及核心目前都在运作；而且这两个机构都没有复制它们。 我们建议在目前的提案中继续履行这些核心职能。这三个项目都有科学的 协同效应。例如，有害的脱硝化反应(项目1)既被气道碱化逆转(项目1) 2)和呼吸道上皮雄激素治疗(项目3)。白介素17，减少呼吸道上皮细胞S- 亚硝硫醇信号转导(项目1)被气道碱化(项目2)和雄激素受体信号转导抑制 (项目3)。白介素4基因的表达似乎受到人类呼吸道碱化的抑制(项目 2)和雄激素受体信号转导(项目3)。这些和相关的相互作用将被详细研究。这个 该计划还具有强大的业务协同效应。每个项目将利用每个核心。尤其是，每个 将使用来自研究支气管镜和生物显微镜核心的数据和样本 哮喘临床试验核心；每个将使用来自原代人类呼吸道细胞培养核心的细胞；每个将依赖于 大量依赖肺生物统计核心进行数据分析；所有项目和核心将由以下人员协调 管理核心。注意到行政核心还将协助所有项目传播数据， 议长和顾问委员会。这三个项目中没有一个能够支持这些核心 作为独立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。