Phenotyping Asthma for Bronchial Thermoplasty: Airway Smooth Muscle Structure and Function

支气管热成形术的哮喘表型分析：气道平滑肌结构和功能

• 批准号: 10018074
• 负责人: Melissa J Suter
• 金额: $ 72.36万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018074
• 关键词: 3-Dimensional; Adrenal Cortex Hormones; Affect; Agonist; Assessment tool; Asthma; Award; Birefringence; Bronchoconstriction; Bronchodilator Agents; Calibration; Catheters; Clinical; Clinical Research; Complex; Computer software; Custom; Detection; Disease; Economic Burden; Epithelial; Epithelium; Etiology; Evaluation; Exhibits; Extrinsic asthma; Fiber; Fibrosis; Functional disorder; Goals; Human; Hyperplasia; Hypertrophy; Imaging Device; Imaging technology; Individual; Inflammation; Knowledge; Link; Measures; Metaplasia; Modeling; Monitor; Morbidity - disease rate; Mucous Membrane; Mucous body substance; Multi-Institutional Clinical Trial; Multicenter Studies; Muscle function; Operative Surgical Procedures; Optical Coherence Tomography; Patients; Phenotype; Physiological; Play; Population; Prevalence; Research; Research Proposals; Resected; Role; Severity of illness; Sheep; Signal Transduction; Structure; Structure of parenchyma of lung; Structure-Activity Relationship; Symptoms; System; Technology; Testing; Therapeutic; Thick; Time; Tissues; Translating; United States; Visualization; airway hyperresponsiveness; airway inflammation; airway obstruction; airway remodeling; asthmatic; asthmatic patient; base; clinical predictors; imaging platform; imaging system; improved; in vivo; individualized medicine; muscular structure; novel; optical imaging; preclinical study; predicting response; prospective; public health relevance; respiratory smooth muscle; response; socioeconomics; targeted treatment; three dimensional structure; validation studies

Project Summary Asthma currently affects over 300 million individuals worldwide and the prevalence is continually increasing. Approximately 10% of asthmatics have uncontrolled or poorly controlled symptoms and it is this population that urgently need improved targeted therapies and management strategies in order to reduce the high morbidity and socio-economic burden, estimated to be 14.7 billion dollars annually in the United States alone. The exact mechanisms behind the pathophysiology of asthma remain uncertain. Airway smooth muscle (ASM) is known to play a critical and multifaceted role, yet our knowledge on the role of ASM in asthma is limited due to an inability to directly visualize and study the 3D structure of ASM, and the relationship to functional bronchoconstriction in patients. The real-time evaluation of ASM is critical in furthering our understanding of the pathophysiology of asthma, for classifying asthma phenotypes, for tailoring treatment, and for assessing and monitoring the response to therapy. In this award we will develop a custom optical imaging platform based on polarization-sensitive optical coherence tomography (PS-OCT) that will enable the accurate quantification of ASM hyperplasia and hypertrophy, epithelial disruption and hypertrophy, subepithelial fibrosis, mucosal thickness increases, mucus metaplasia, in vivo. We will develop and validate novel dual-layer calibrating catheters that will enable accurate assessment of tissue fiber orientation and birefringence signal intensity. We will additionally develop and validate automated calibration and processing software that will provide real-time visualization of ASM in vivo. These technological advancements will enable us to begin to answer important questions linking remodeling changes in airway wall structure with physiologic function. We will conduct a preclinical study in a sheep model of allergic asthma to test our hypothesis that remodeling plays both a protective and provocative role in bronchoconstriction, and that the presence of inflammation greatly increases bronchoconstriction. We will further translate this technology into the clinical setting in a multicenter clinical trial aimed at using our PS-OCT imaging system to phenotype asthma and to predict the response to bronchial thermoplasty. The unprecedented ability to study both the 3D structure of airway smooth muscle (ASM) and it’s function in vivo is likely to transform the study of asthma in patients in phenotyping populations, for therapy guidance, and in research endeavors aimed at studying the true role of ASM in asthma.

项目摘要 目前，哮喘影响着全球超过3亿个人，并且患病率正在不断增加。 大约10％的哮喘患者没有控制或控制症状不良，正是这种人口是 迫切需要改进目标疗法和管理策略，以减少高病态 和社会经济负担估计仅在美国每年为147亿美元。 哮喘剩余的病理生理背后的机制不确定。 扮演关键和多方面的角色，但是我们对哮喘作用的了解是有限的 无法直接可视化和研究ASM的3D结构，以及与功能的关系 患者的支气管收缩。 哮喘的病理生理学，用于分类哮喘表型，定制治疗和评估 并监视对该奖项的反应。 明天（PS-OCT）对极化敏感的光学相干性 ASM增生和肥大，上皮破坏和肥大，上皮纤维化，粘膜 厚度增加，粘液质量，体内我们将开发并验证新型双层校准 可以准确评估组织纤维方向和双重信号强度的导管 将在拟进行的开发和验证自动化的静脉自由储存的静脉自由储存软件，该软件将提供实时 ASM在体内的可视化。 问题链接重塑气道墙结构的变化，我们将进行一次。 在Allgic哮喘的绵羊模型中，临床前研究测试了我们的假设，即重塑既有重塑又有作用 保护性和挑衅性在支气管收缩中的作用，并且存在炎症的存在 支气管收缩。 旨在将我们的PS-OCT成像系统用于表型哮喘，并预测对支气管的反应 热置术。 体内功能可能会改变患者哮喘的研究，以进行治疗 指导和研究旨在研究ASM在哮喘中的真正作用。