Mitochondrial translocator protein: a target for bronchodilation

线粒体易位蛋白：支气管扩张的靶点

• 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
• 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

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.

项目概要 哮喘的有效治疗需要调节气道平滑肌 (ASM) 收缩性以预防或 逆转支气管收缩。这主要是通过使用直接支气管扩张剂（例如β-激动剂）、抗- 单独或联合使用炎症剂（例如皮质类固醇）。然而，有效的管理是 缺乏，因为估计 55% 的哮喘患者控制不佳。目前所有的支气管扩张药物均具有 与功效或安全性相关的限制。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/支气管保护的一种手段。我们的中央 假设可以开发出强效、有效的 TSPO 激动剂并将其用作有效的 支气管扩张/支气管保护药物。提出了三个目标来检验这一假设。在目标 1 中，使用 体外（初级气道平滑肌细胞；ASM），离体（小鼠和人类环和精密切割肺切片）， 和体内模型（smTspo-/- 小鼠），我们将建立 TSPO 作为药物靶点来促进 ASM 的松弛。 在目标 2 中，我们将通过评估角色来确定 TSPO 调节 ASM 收缩的机制基础 PKA 以及线粒体 Ca2+ 和 ROS，对已知调节跨桥循环的信号事件（调节 肌球蛋白轻链 20 和肌球蛋白磷酸酶磷酸化）或肌动蛋白聚合状态（F/G 肌动蛋白比率）。 最后，在目标 3 中，我们将采用分子建模来设计和合成 TSPO 的新配体，其中 重点是生产具有优异结合特性和提高疗效的新药物。这些 将在目标 1 中使用的细胞和组织模型系统中进行测试。拟议的研究代表了一项创新 建立哮喘管理策略的方法，克服目前疗效和方法的局限性 安全。此外，所提出的机制研究将为如何最佳地瞄准目标提供新的见解。 线粒体调节 ASM 中的收缩信号和功能。