Mitochondrial translocator protein: a target for bronchodilation

线粒体易位蛋白：支气管扩张的靶点

基本信息

批准号：
10298047
负责人：
Ajay Nayak
金额：
$ 40.43万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298047
关键词：
Actins Adrenal Cortex Hormones Agonist Anti-Inflammatory Agents Architecture Asthma Basic Science Benzodiazepine Receptor Benzodiazepines Binding Biologic Development Biological Models Biological Response Modifier Therapy Biology Bronchoconstriction Bronchodilation Bronchodilator Agents CRISPR/Cas technology Cavia Cell model Cells Contracts Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytoskeleton Development Event G Actin G-Protein-Coupled Receptors GPR68 gene Goals Health Care Costs Human In Vitro Individual Knock-out Lead Ligands Link Lorazepam Lung Maintenance Malignant neoplasm of ovary Mediating Methodology Mitochondria Mitochondrial Proteins Modeling Mus Muscle Muscle Contraction Muscle relaxation phase Myosin Regulatory Light Chains Obstructive Lung Diseases Peripheral Pharmaceutical Preparations Pharmacology Phosphorylation Play Property Proteins Protons Reactive Oxygen Species Regulation Relaxation Role Safety Signal Transduction Slice Small Interfering RNA Smooth Muscle Smooth Muscle Myocytes Specificity Stimulus Structure System Testing Therapeutic Tissue Model Tissues Traction United States airway inflammation airway remodeling asthmatic asthmatic patient base design drug development druggable target improved in vivo in vivo Model innovation insight knock-down molecular modeling myosin phosphatase neurosteroids novel novel strategies novel therapeutics polymerization prevent protein activation respiratory smooth muscle therapeutic target tool virtual

项目摘要

Project Summary Effective management of asthma requires regulating airway smooth muscle (ASM) contractility to prevent or reverse bronchoconstriction. This is primarily achieved by use of direct bronchodilators (e.g., β-agonists), by anti- inflammatory agents (e.g., corticosteroids) either alone or in combination. However, effective management is lacking, as an estimated 55% of all asthmatics have suboptimal control. All current bronchodilator drugs have limitations which respect to efficacy or safety. We propose a novel approach of targeting a mitochondrial protein, the 18 kDa Translocator Protein (TSPO), as a means of bronchodilation/bronchoprotection. Our central hypothesis is that potent, efficacious agonists of TSPO can be developed and employed as effective bronchodilatory/bronchoprotection drugs. Three aims are proposed to test this hypothesis. In Aim 1, using in vitro (primary airway smooth muscle cells; ASM), ex vivo (murine and human rings and precision cut lung slices), and in vivo models (smTspo-/- mice), we will establish TSPO as a druggable target to promote relaxation of ASM. In Aim 2, we will determine the mechanistic basis of TSPO regulation of ASM contraction by assessing the roles of PKA, and mitochondrial Ca2+ and ROS, on signaling events known to regulate cross bridge cycle (regulatory myosin light chain 20 and myosin phosphatase phosphorylation) or actin polymerization state (F/G actin ratio). Lastly, in Aim 3 we will employ molecular modeling to design and synthesize new ligands for TSPO, with an emphasis on generating new drugs that demonstrate superior binding properties and improved efficacy. These will be tested in cell and tissue model systems employed in Aim 1. The proposed studies represent an innovative approach to establish an asthma management strategy that overcomes the current limitations of efficacy and safety. Moreover, the proposed mechanistic studies will provide new insight into how to optimally target the mitochondria to regulate contractile signaling and function in ASM.

项目摘要有效管理哮喘需要调节气道平滑肌（ASM）收缩性才能预防或反向支气管收缩。这主要是通过使用直接支气管扩张剂（例如β-激动剂）来实现的单独或组合炎症剂（例如皮质类固醇）。但是，有效的管理是缺乏，因为估计所有哮喘患者中有55％具有次优控制。所有当前的支气管扩张剂药物都有涉及效率或安全的限制。我们提出了一种靶向线粒体蛋白的新方法， 18 kDa易位蛋白（TSPO），作为支气管扩张/支气管造影的一种手段。我们的中心假设是，可以开发和使用潜在的，有效的TSPO激动剂作为有效支气管扩张/支气管保护药物。提出了三个目的来检验这一假设。在AIM 1中，使用体外（主要气道平滑肌细胞； ASM），离体（鼠和人环以及精度切割肺切片），肺切片）和体内模型（SMTSPO - / - 小鼠），我们将建立TSPO作为促进ASM放松的可药物目标。在AIM 2中，我们将通过评估角色来确定ASM收缩的TSPO调节的机理基础 PKA和线粒体Ca2+和ROS的信号事件已知，已知的调节跨桥周期（调节性调节）肌球蛋白轻链20和肌球蛋白光磷酸酶光疗）或肌动蛋白聚合态（F/G肌动蛋白比）。最后，在AIM 3中，我们将采用分子建模来设计和合成TSPO的新配体，并使用强调生成新药物，这些药物表现出优异的结合特性和提高效率。这些将在AIM 1中采用的细胞和组织模型系统中进行测试。拟议的研究代表了创新的研究建立哮喘管理策略，以克服当前效率的局限性和安全。此外，拟议的机械研究将为如何最佳针对目标提供新的见解线粒体调节ASM的收缩信号传导和功能。