Therapeutic Potentiation of Bronchial Dilatation

支气管扩张的治疗增强作用

基本信息

批准号：
8259736
负责人：
Jeffrey J Fredberg
金额：
$ 45.57万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8259736
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Acetylcholine Actins Adrenal Cortex Hormones Adrenergic Agonists Adverse effects Affect Asthma Atomic Force Microscopy Attention Biological Assay Boa Breathing Bronchoconstriction Bronchodilator Agents Calcium Canis familiaris Cardiac Cells Cessation of life Chemosensitization Complex Contracts Developed Countries Dilatation - action Dose Drug Controls Drug Delivery Systems Drug effect disorder Environmental air flow Evaluation Exposure to Failure Filament Freezing Generations Guidelines HSPB1 gene Human Individual Inflammation Instruction Intervention Length Lung Microfilaments Minority Muscle Muscle Cells Muscle Contraction Myosin ATPase Myosin Light Chains Obstruction Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Population Principal Investigator Public Health Relative (related person)Risk Role Screening procedure Side Signal Pathway Slice Smooth Muscle Smooth Muscle Myocytes Smooth Muscle Myosins Solutions Staging Subgroup Symptoms Testing Therapeutic Therapeutic Effect Thick Time Tomogram Traction Work of Breathing airway inflammation base design high throughput screening improved meetings novel novel strategies novel therapeutics omalizumab polymerization reconstruction release of sequestered calcium ion into cytoplasm respiratory smooth muscle skeletal therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Given its central role in asthmatic airflow obstruction, airway smooth muscle (ASM) contraction has long received attention as a therapeutic target, with strategies directed at relaxing ASM or ablating ASM altogether. Here, we propose an entirely novel approach to relieving airflow obstruction in asthma. Our strategy is to impair the ability of contracted ASM to remain shortened after contraction has occurred. While ASM that has contracted against a steady load can remain shortened indefinitely, ASM contracting against a fluctuating load first shortens then relengthens; such force fluctuation-induced relengthening (FFIR) can be quite substantial and can be further enhanced pharmacologically. In the intact lung, ASM is constantly exposed to force fluctuations imposed by tidal breathing. The key premise of this application is that drugs targeted specifically to exaggerate breathing-induced FFIR should release ASM's squeeze on the airway lumen and thus relieve bronchoconstriction. Our objective is to identify and evaluate compounds that target this extremely potent but largely unstudied bronchodilatory pathway. Preliminary studies disclose disruption of actin-myosin-actin connectivity (AMAC) as an attractive strategy for enhancing FFIR. In isolated ASM, interventions that reduce the polymerization of actin or myosin filaments both reduce AMAC and promote FFIR. In a staged screening design, we will use large scale high throughput primary assays to identify novel or already-in-human compounds that: 1) inhibit polymerization of myosin into thick myofilaments; and/or 2) reduce force generation by cultured human ASM. A novel low throughput assay will then be used to test which of these compounds potentiates FFIR or inhibits bronchoconstriction in intact airways within precision- cut thin slices of human lungs. Finally, we will evaluate mechanisms of drug action by quantifying myofila}} ment lengths in flash frozen control and drug-treated intact human ASM using 3D reconstructions of myofila}} ment ultrastructure from EM tomograms, and by assessing potential alternative mechanisms of drug action, including alteration of intracellular calcium mobilization, MLC20 phosphorylation, and/or HSP27 phosphoryl}} ation. Our results should identify novel drugs for asthma that potentiate FFIR or inhibit bronchoconstriction. RELEVANCE (See instructions): The objective of this project is to identify drugs that could exert a novel therapeutic effect in asthma - by promoting the rapid reversal of bronchoconstriction. This approach is fully complementary to current therapeutic approaches aimed at suppressing airway inflammation or relaxing airway muscle and so, if developed successfully, should add an entirely new therapeutic strategy to existing asthma therapies.

描述（由申请人提供）：鉴于其在哮喘气流阻塞中的核心作用，气道平滑肌（ASM）收缩长期以来一直关注作为治疗目标，并完全旨在放松ASM或完全消融ASM。在这里，我们提出了一种完全新颖的方法来缓解哮喘中的气流阻塞。我们的策略是损害收缩发生后签约的ASM缩短的能力。尽管针对稳定载荷收缩的ASM可以无限期地缩短，但ASM首先缩短了与波动载荷的收缩，然后将其关联度缩短。这种力波动引起的关系加长（FFIR）可能是相当大的，可以进一步增强药理。在完整的肺中，ASM不断暴露于潮汐呼吸引起的力波动。该应用程序的主要前提是，专门针对夸大呼吸引起的FFIR的药物应释放ASM在气道管腔上的挤压，从而缓解支气管收缩。我们的目标是识别和评估针对这种极有效但在很大程度上未研究的支气管扩张途径的化合物。初步研究揭示了肌动蛋白 - 肌球蛋白 - 肌动蛋白连接性（AMAC）的破坏，这是增强FFIR的有吸引力的策略。在孤立的ASM中，减少肌动蛋白或肌球蛋白丝聚合的干预措施均减少AMAC并促进FFIR。在分阶段的筛选设计中，我们将使用大规模的高吞吐量主要测定法来识别以下新颖或已经是人类的化合物：1）抑制肌球蛋白的聚合成厚的肌细胞。和/或2）通过培养的人类ASM减少力量产生。然后，将使用一种新型的低通量测定法测试这些化合物中的哪种化合物会增强FFIR或在人类肺的精确切割薄片中抑制完整气道中的支气管收缩。最后，我们将通过量化闪光灯冷冻控制和药物治疗的完整人类ASM中的肌膜作用的机制来评估药物作用的机制，该长度使用EM Tomograms的3D重建进行了超微结构的3D重建，并通过评估药物作用的潜在替代机制，包括内脑含量和脑内含量的替代机制。磷酸}}}}。我们的结果应确定增强FFIR或抑制支气管收缩的哮喘的新药物。相关性（请参阅说明）：该项目的目的是通过促进支气管收缩的快速逆转来确定可以在哮喘中发挥新型治疗作用的药物。这种方法完全补充了旨在抑制气道炎症或放松气道肌肉的当前治疗方法，因此，如果成功发展，应该为现有的哮喘疗法增加一种全新的治疗策略。