Scientific innovation for personalized severe asthma management

个性化重症哮喘管理的科学创新

• 批准号: 10662235
• 负责人: Benjamin Gaston
• 金额: $ 240.56万
• 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/10662235
• 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; IL17 gene; IL4 gene; In Vitro; Indiana; Inflammation; Inhalation; Institution; 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.

项目总结/文摘

项目成果

Defining and Promoting Pediatric Pulmonary Health: A NHLBI Workshop Executive Summary.

定义和促进儿科肺部健康：NHLBI 研讨会执行摘要。

• DOI: 10.1542/peds.2023-062292b
• 发表时间: 2023
• 期刊: Pediatrics
• 影响因子: 8
• 作者: Chmiel,JamesF;Natarajan,Aruna;Banerjee,Koyeli;Fessel,Josh;Lachowicz-Scroggins,Marrah;Laposky,Aaron;Davis,StephanieD
• 通讯作者: Davis,StephanieD

Effects of pH alteration on respiratory syncytial virus in human airway epithelial cells.

pH 变化对人呼吸道上皮细胞中呼吸道合胞病毒的影响。

• DOI: 10.1183/23120541.00404-2022
• 发表时间: 2023
• 期刊: ERJ open research
• 影响因子: 4.6
• 作者: Saunders,JessicaL;Daniels,IvanaA;Edwards,TaiyaL;Relich,RyanF;Zhao,Yi;Smith,LauraA;Gaston,BenjaminM;Davis,MichaelD
• 通讯作者: Davis,MichaelD

Antigen stasis and airway nitrosative stress in human primary ciliary dyskinesia.

人类原发性纤毛运动障碍中的抗原停滞和气道亚硝化应激。

• DOI: 10.1152/ajplung.00208.2022
• 发表时间: 2024
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Gaston,Benjamin;Smith,LauraA;Davis,MichaelD;Saunders,Jessica;Daniels,Ivana;Horani,Amjad;Brody,StevenL;Giddings,Olivia;Zhao,Yi;Marozkina,Nadzeya
• 通讯作者: Marozkina,Nadzeya