Novel Molecular Mechanisms Promote GPCR-Induced Bronchodilation in Asthma

新型分子机制促进 GPCR 诱导的哮喘支气管扩张

• 批准号: 10478318
• 负责人: Reynold Alexander Panettieri
• 金额: $ 5.59万
• 依托单位: RUTGERS BIOMEDICAL/HEALTH SCIENCES-RBHS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478318
• 关键词: Address; Agonist; Arrestins; Asthma; Benzodiazepine Receptor; Benzodiazepines; Biology; Biophysics; Bronchoconstriction; Bronchodilation; Bronchodilator Agents; Cell model; Collaborations; Coupling; G-Protein-Coupled Receptors; GPR68 gene; Goals; Health; Human; Inflammation; Libraries; Link; Mediating; Molecular; Muscle Contraction; Peripheral; Pharmacology; Physiology; Plant Roots; Program Research Project Grants; Receptor Activation; Regulation; Research; Research Personnel; Role; Signal Transduction; Taste Buds; Tissue Model; airway hyperresponsiveness; airway inflammation; beta-arrestin; desensitization; drug candidate; high throughput screening; improved; new therapeutic target; novel; programs; respiratory smooth muscle; small hairpin RNA; small molecule libraries; targeted treatment; training project; virtual screening; whole genome

Project Summary Our renewal of this interdisciplinary PPG remains focused on the theme of novel molecular mechanisms to inhibit human airway smooth muscle (HASM) contraction and promote bronchodilation within the context of airway inflammation and asthma. The principal hypothesis states that G protein coupled receptor (GPCR) desensitization and unbiased signaling limits the efficacy of conventional bronchodilators, such that targeting desensitization mechanisms, promoting biased agonism, circumventing mechanisms of ASM hypercontractility/airway hyperresponsiveness (AHR), or engaging novel bronchorelaxant mechanisms in HASM will provide superior therapy for asthma. Each Project addresses this hypothesis by either: 1) optimizing pro- relaxant signaling abilities of one of 3 different GPCRs using strategies rooted in cutting edge biophysical or pharmacological approaches; or 2) establishing novel intracellular targets mediating inflammation-driven AHR and increased GPCR pro-contractile signaling. Project 1 will establish the mechanisms by which TGF-β1 modulates excitation-contraction (EC) coupling of HASM and thereby identify novel therapeutic targets linked to both AHR and increased GPCR-mediated contraction. Project 2 will advance the recent discovery of bitter taste receptors (TAS2R) as novel bronchodilators clarifying the role of TAS2R subtypes in HASM, their mode of regulation and means to improve their efficacy through biased agonism. Project 3 will characterize the molecular basis of β2AR biased signaling to develop compounds that mediate Gs-biased signaling through either inhibition of β-arrestin interaction with the agonist-occupied β2AR (arrestin-biased negative allosteric modulators (NAMs)) or by enhancing coupling of the β2AR to Gs (biased orthosteric agonists). Project 4 will similarly characterize the mechanisms underlying biased signaling of OGR1, develop new biased OGR1 benzodiazepine derivatives with superior ability to bronchodilate, and determine the relative contribution of and mechanisms underlying peripheral benzodiazepine receptor activation by candidate drugs. The four projects will be supported by Core A that will use high through-put screening of small molecule libraries, whole genome, pooled shRNA libraries and virtual screening approaches to identify targets and effectors of bronchodilation. Core B will provide all de-identified human cell and tissue models to study novel mechanisms regulating EC coupling in HASM. Core C will provide administrative support for the program. The strengths of this Program are the common focus on a single theme and the productive working relationship among investigators with the ability to apply cutting edge GPCR biology to key questions in asthma biology and pharmacology.

项目总结