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

基本信息

批准号：
10887634
负责人：
Reynold Alexander Panettieri
金额：
$ 6.02万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10887634
关键词：
Actins Address Affect Agonist Airway Disease Arrestins Asthma Basic Science Benzodiazepine Receptor Benzodiazepines Biological Products Biology Biophysics Bronchoconstriction Bronchodilation Bronchodilator Agents Cell model Cell surface Clinical Coupling Development Disease Funding G protein coupled receptor kinase G-Protein-Coupled Receptors GPR68 gene Goals Human Inflammation Libraries Ligands Link Mediating Molecular Muscle Contraction Muscle relaxation phase Outcome Patients Peripheral Pharmaceutical Preparations Pharmacology Polymers Productivity Proteins Receptor Activation Regulation Research Research Personnel Role Safety Signal Pathway Signal Transduction Tachyphylaxis Taste Buds Testing Therapeutic Tissue Model Translational Research Treatment Efficacy airway hyperresponsiveness airway inflammation beta-arrestin biophysical techniques cohort desensitization design drug candidate empowerment high throughput screening improved insight new therapeutic target novel novel therapeutics pharmacologic polymerization prevent programs receptor respiratory smooth muscle small hairpin RNA small molecule libraries therapeutic target therapeutically effective virtual screening whole genome

项目摘要

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.

项目摘要我们对这个跨学科PPG的续签仍然集中在新的分子机制的主题上抑制人类气道平滑肌（HASM）收缩，并在气道注射和哮喘。主要假设指出G蛋白偶联受体（GPCR）脱敏和公正的信号传导限制了常规支气管扩张剂的效率，以便靶向脱敏机制，促进偏见的激动剂，规避ASM的机制超重应力（AHR）或引人入胜的新型支气管乳糖机制 HASM将为哮喘提供卓越的疗法。每个项目都通过以下任务解决这一假设：1）使用植根于尖端生物物理的策略或药理方法；或2）建立介导注射驱动的AHR的新型细胞内靶标增加了GPCR促收缩信号。项目1将建立TGF-β1调节兴奋 - 收缩（EC）耦合的机制 HASM，从而确定与AHR相关的新型治疗靶标和GPCR介导的增加收缩。项目2将推动最近发现苦味受体（TAS2R）作为新颖的发现支气管扩张剂阐明了TAS2R亚型在HASM中的作用，其调节方式和改进的手段他们通过偏见的激动剂的效率。项目3将表征β2AR信号传导的分子基础通过抑制β-arrestin的相互作用，可以开发介导GS偏置信号传导的化合物激动剂占用的β2AR（抑制了偏置的负变构调节剂（NAM））或通过增强偶联 β2AR至GS（偏置的正常激动剂）。项目4将类似地表征偏见的机制 OGR1的信号传导，开发具有较高支气管扩张能力的新的有偏见的OGR1苯二氮卓类化衍生物，并且通过确定外周二氮卓受体受体激活的相对贡献和机制的相对贡献候选药物。这四个项目将得到核心A的支持，该项目将使用小分子的高贯穿筛选图书馆，整个基因组，合并的shRNA库和虚拟筛选方法，以识别目标和支气管扩张的效应器。核心B将为研究新颖的人类细胞和组织模型提供新的。在HASM中进行EC耦合的机制。核心C将为该计划提供管理支持。该计划的优势是对单个主题和富有成效的工作关系的普遍关注能够将尖端GPCR生物学应用于哮喘生物学和药理学的关键问题的研究者。