Preclinical investigation of tissue barrier function with HP-129Xe MRI

使用 HP-129Xe MRI 进行组织屏障功能的临床前研究

• 批准号: 2869744
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2869744
• 关键词: Preclinical; investigation; tissue; barrier; function

Hyperpolarised 129-xenon (HP-129Xe) gas MRI of the lung produces distinct spectral signals from airspace, blood-air barrier and capillary red blood cell compartments. This established non-invasive clinical imaging technique provides a unique potential mechanism for determining the efficiency of molecular diffusion across the blood-air barrier via a range of biomarkers. Despite the potential importance of these biomarkers in diagnosing and monitoring important lung diseases associated with high morbidity and mortality, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), asthma and post-COVID-19 interstitial lung disease, this approach suffers from a lack of biological validation, leaving their interpretation insecure. The studentship will address this need by preclinical application of HP-129Xe MRI in small animal models of fibrotic and inflammatory lung disease to assess blood-air barrier function and response to pharmacological intervention. Results will be validated against conventional lung imaging modalities such as CT, PET or SPECT, and related to established measures of lung structure (tissue sample histology) and function (pulmonary function tests (PFTs)). Investigations of tissue barrier function with HP-129Xe MRI may extend beyond the lungs to the intestines and brain. Objectives All objectives are expected to result in peer reviewed publications for the prospective student: Develop methods for quantitative assessment of blood-air barrier structure & function using HP- 129Xe MRI in small animal models of pulmonary fibrosis (e.g. bleomycin) and inflammation (e.g. elastase or LPS instillation) Make new mechanistic discoveries by relating HP-129Xe MRI measurements to disease pathogenesis and progression, and by observing response to pharmacological intervention. For example, selective modulation of molecular targets of interest, such as TRPV4 (Transient receptor potential cation channel subfamily V member 4) might provide insight to disease mechanisms of potential therapeutic utility Validation of measurements against CT with PET and/or SPECT, PFTs and histological analyses (e.g. histology, -omics, flow cytometry or CyTOF) Optimise clinical data acquisition and analysis protocols for future translation of HP-129Xe MRI findings to human volunteers and patient studies Explore use of preclinical HP-129Xe MRI for tissue barrier and transport assessment in other organ sites such as the intestines and brain

肺部的超极化129-氙气(HP-129Xe)气体磁共振成像从空气空间、血-空气屏障和毛细血管红血球隔间产生明显的光谱信号。这一成熟的非侵入性临床成像技术提供了一种独特的潜在机制，可以通过一系列生物标志物来确定分子通过血-气屏障的扩散效率。尽管这些生物标志物在诊断和监测与高发病率和高死亡率相关的重要肺部疾病方面具有潜在的重要性，包括慢性阻塞性肺疾病、特发性肺纤维化、囊性纤维化、哮喘和新冠肺炎后间质性肺疾病，但这种方法缺乏生物学验证，使得它们的解释不安全。该项目将通过在纤维化和炎症性肺部疾病的小动物模型中临床前应用HP-129Xe MRI来评估血-气屏障功能和对药物干预的反应来满足这一需求。结果将与CT、PET或SPECT等常规肺部成像方式以及肺结构(组织样本组织学)和功能(肺功能测试(PFT))的既定测量相关地进行验证。HP-129Xe磁共振成像对组织屏障功能的研究可能会从肺扩展到肠和脑。目的：通过HP-129Xe MRI定量评估肺纤维化(如博莱霉素)和炎症(如弹性酶或脂多糖滴注)小动物模型中的血-气屏障结构和功能，通过将HP-129Xe MRI测量与疾病的发生和发展联系起来，并通过观察对药物干预的反应，获得新的机制发现。例如，对感兴趣的分子靶点的选择性调制，如TRPV4(瞬时受体潜在型阳离子通道亚家族V成员4)，可能提供潜在治疗效用的疾病机制的洞察。通过PET和/或SPECT、PFTs和组织学分析(例如，组织学、组学、流式细胞术或细胞TOF)对照CT的测量验证，优化临床数据采集和分析方案，用于将来将HP-129Xe MRI结果翻译给人类志愿者和患者研究探索临床前HP-129Xe MRI用于组织屏障和其他器官部位(如肠和脑)的传输评估