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

项目摘要 哮喘目前影响全世界超过3亿人，并且患病率持续增加。 大约10%的哮喘患者有不受控制或控制不佳的症状， 迫切需要改进的靶向治疗和管理策略，以降低高发病率 据估计，仅美国每年就有147亿美元的社会经济负担。的确切 哮喘的病理生理学机制仍然不确定。已知气道平滑肌（ASM） 发挥关键和多方面的作用，但我们对ASM在哮喘中的作用的认识是有限的， 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。ASM的实时评估对于加深我们对以下方面的理解至关重要： 哮喘的病理生理学，用于分类哮喘表型，用于定制治疗，以及用于评估 并监测对治疗的反应。在这个奖项中，我们将开发一个定制的光学成像平台， 偏振敏感光学相干断层扫描（PS-OCT），这将使准确的量化， ASM增生和肥大、上皮破坏和肥大、上皮下纤维化、粘膜 在体内，厚度增加，粘液化生。我们将开发和验证新的双层校准 这些导管将能够准确评估组织纤维方向和双折射信号强度。我们 此外，还将开发和验证自动校准和处理软件， ASM在体内的可视化。这些技术进步将使我们能够开始回答重要的 将气道壁结构的重塑变化与生理功能联系起来的问题。我们将进行 一项在绵羊过敏性哮喘模型中进行的临床前研究，以验证我们的假设，即重塑在哮喘中起着重要作用， 在支气管收缩中的保护和激发作用，并且炎症的存在大大增加 支气管收缩我们将在多中心临床试验中进一步将这项技术转化为临床环境 目的是使用我们的PS-OCT成像系统对哮喘进行表型分析， 热成形术研究气道平滑肌（ASM）的3D结构及其 体内功能可能会改变哮喘患者表型人群的研究， 指导，并在研究努力，旨在研究真正的作用ASM在哮喘。

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.