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: 10653090
• 负责人: Ajay Nayak
• 金额: $ 39.03万
• 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/10653090
• 关键词: Actins; Adrenal Cortex Hormones; Agonist; Anti-Inflammatory Agents; Architecture; Asthma; Basic Science; Benzodiazepine Receptor; Benzodiazepines; Binding; 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; Homeostasis; Human; In Vitro; Individual; Knockout Mice; Ligands; Link; Lorazepam; Lung; Maintenance; Mediating; Methodology; Mitochondria; Mitochondrial Membrane Protein; Mitochondrial Proteins; Modeling; Mus; Muscle; Muscle Contraction; Muscle relaxation phase; Myosin Regulatory Light Chains; Obstructive Lung Diseases; Peripheral; Pharmaceutical Preparations; Phosphorylation; Polymers; 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; Trachea; Traction; United States; airway inflammation; airway remodeling; antagonist; asthmatic; asthmatic patient; 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; pharmacologic; 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.

项目摘要 哮喘的有效治疗需要调节气道平滑肌(ASM)的收缩能力，以防止或 逆转支气管收缩。这主要是通过使用直接的支气管扩张剂(例如，β激动剂)，通过抗- 发炎剂(例如，皮质类固醇)单独或组合使用。然而，有效的管理是 缺乏，因为估计55%的哮喘患者的控制能力不佳。目前所有的支气管扩张药物都有 在有效性或安全性方面的局限性。我们提出了一种新的靶向线粒体蛋白的方法， 18 kDa转位蛋白(TSPO)，作为一种支气管扩张/保护手段。我们的中央 假设TSPO的强效激动剂可以被开发和使用为有效的 扩张/保护支气管的药物。为了检验这一假设，本文提出了三个目标。在目标1中，使用 体外(原代呼吸道平滑肌细胞；ASM)，体外(小鼠和人的肺环和精密切割的肺切片)， 在体内模型(smTspo-/-小鼠)中，我们将建立TSPO作为促进ASM松弛的药物靶点。 在目标2中，我们将通过评估TSPO对ASM收缩的作用来确定TSPO调节ASM收缩的机制基础 PKA、线粒体钙和ROS对已知调节跨桥循环(调节性)的信号事件 肌球蛋白轻链20和肌球蛋白磷酸酶磷酸化)或肌动蛋白聚合态(F/G肌动蛋白比率)。 最后，在目标3中，我们将使用分子模拟来设计和合成TSPO的新配体，其中 强调开发具有优异结合性能和提高疗效的新药。这些 将在AIM 1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个创新的 建立哮喘管理策略的方法，以克服目前疗效和 安全。此外，拟议的机械论研究将为如何以最佳方式瞄准 线粒体调节ASM中的收缩信号和功能。