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Project 4 - OGR1- and TSPO- dependent mechanisms mediated by benzodiazepines affecting ASM contraction

项目 4 - 苯二氮卓类药物介导的 OGR1 和 TSPO 依赖性机制影响 ASM 收缩

基本信息

批准号：
10683131
负责人：
RAYMOND B. PENN
金额：
$ 37.31万
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/10683131
关键词：
Affect Arrestins Asthma Benzodiazepine Receptor Benzodiazepines Binding Biological Assay Biology Bronchodilation Bronchodilator Agents Cell Surface Receptors Cells Collaborations Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Drug Targeting Exhibits Follow-Up Studies G-Protein-Coupled Receptors GPR68 gene GTP-Binding Proteins Goals Histidine Ligands Lorazepam Mediating Methodology Mitochondria Modeling Molecular Muscle Contraction Muscle function New Agents Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacology Physiological Program Research Project Grants Proliferating Property Proteins Protons Publishing Receptor Signaling Relaxation Resources Signal Pathway Signal Transduction Specificity Structure System Testing Therapeutic Tissues Treatment Efficacy arm asthmatic airway smooth muscle cell type design drug synthesis efficacy testing extracellular improved in vivo Model insight molecular modeling mutant novel novel therapeutics protein activation protein function receptor respiratory smooth muscle small molecule

项目摘要

Project Summary In the previous cycle we characterized the ability of certain benzodiazepines, in cooperation with decreased extracellular pH, to regulate airway smooth muscle (ASM) signaling and function via activation of the proton- sensing G protein-coupled receptor (GPCR) OGR1 (Ovarian cancer G-protein coupled receptor 1 aka GPR68). Importantly, we discovered that the multiple signaling pathways activated downstream of OGR1 could be selectively activated (i.e., biased) to produce differential effects on ASM contraction and proliferation. In this second cycle we propose to: 1) delineate the mechanisms by which the biasing of OGR1 signaling occurs; 2) detail an additional, mitochondrial-dependent effector arm of benzodiazepines that also inhibits ASM contraction; and 3) employ modeling to develop more efficacious benzodiazepine-like drugs that target these mechanisms. These goals will be achieved through 3 Specific Aims. In Aim 1 we will employ cell-based and integrative models of ASM contraction to clarify the how different benzodiazepines promote specific OGR1- and peripheral benzodiazepine receptor- signaling to regulate ASM contraction. In Aim 2 will establish the mechanistic basis of biased OGR1 signaling by assessing structure-function properties of OGR1 that dictate G protein coupling, and the biasing function of arrestins. In Aim 3 in collaboration with Core A we will employ molecular modeling to design new allosteric modulators to bias OGR1 signaling towards Gs/cAMP/PKA pathway activation and the associated therapeutic benefits, using the signaling and functional assays employed in Aims 1 and 2 to guide development and identify the most efficacious drugs. By establishing mechanisms mediating qualitative signaling by OGR1 and developing new agents that optimally bias OGR1 and promote bronchodilation, we will significantly advance the fields of both receptor biology and asthma therapeutics.

项目摘要在上一个周期中，我们的特点是某些苯二氮卓类药物的能力，在合作减少细胞外pH值，通过激活质子调节气道平滑肌（ASM）信号传导和功能。敏感G蛋白偶联受体（GPCR）OGR 1（卵巢癌G蛋白偶联受体1，又名GPR 68）。重要的是，我们发现OGR 1下游激活的多种信号通路可能是选择性激活（即，偏倚）对ASM收缩和增殖产生不同的影响。在这第二个周期，我们建议：1）描绘OGR 1信号发生偏置的机制; 2）详细描述了苯二氮卓类药物的一个额外的、神经依赖性的效应臂，该效应臂也抑制ASM收缩; 和3）采用建模来开发针对这些机制的更有效的苯二氮卓类药物。这些目标将通过三个具体目标来实现。在目标1中，我们将采用基于细胞的综合模型的ASM收缩，以澄清不同的苯二氮卓类药物如何促进特定的OGR 1-和外周苯二氮卓受体-信号转导调节ASM收缩。在目标2中，将建立通过评估决定G蛋白偶联的OGR 1的结构-功能特性来偏置OGR 1信号传导，以及抑制蛋白的偏置功能。在Aim 3中，与Core A合作，我们将采用分子建模，设计新的变构调节剂以将OGR 1信号传导偏向Gs/cAMP/PKA途径激活和相关的治疗益处，使用目的1和2中采用的信号传导和功能测定来指导开发和鉴定最有效的药物。通过建立机制，通过OGR 1的信号传导和开发新的药物，最佳地偏向OGR 1和促进支气管扩张，我们将显著推进受体生物学和哮喘治疗学领域。