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

肺的超极化129氙（HP-129 Xe）气体MRI从空气空间、血液-空气屏障和毛细血管红细胞室产生不同的光谱信号。这种已建立的非侵入性临床成像技术提供了一种独特的潜在机制，用于通过一系列生物标志物确定分子扩散穿过血液-空气屏障的效率。尽管这些生物标志物在诊断和监测与高发病率和死亡率相关的重要肺部疾病（包括慢性阻塞性肺疾病（COPD）、特发性肺纤维化（IPF）、囊性纤维化（CF）、哮喘和COVID-19后间质性肺病）方面具有潜在重要性，但这种方法缺乏生物学验证，使其解释不安全。该奖学金将通过在纤维化和炎症性肺病的小动物模型中应用HP-129 MRI的临床前应用来解决这一需求，以评估血液-空气屏障功能和对药物干预的反应。结果将根据常规肺部成像模式（如CT、PET或SPECT）进行验证，并与肺结构（组织样本组织学）和功能（肺功能测试（PFT））的既定测量相关。使用HP-129 MRI对组织屏障功能的研究可能会从肺部扩展到肠道和大脑。目标所有的目标预计将导致同行评审的出版物为未来的学生：建立肺纤维化小动物模型的HP-129磁共振定量评价方法（例如博来霉素）和炎症（例如，弹性蛋白酶或LPS滴注）通过将HP-129 β MRI测量与疾病发病机制和进展相关，并通过观察对药物干预的反应。例如，选择性调节感兴趣的分子靶标，如TRPV 4（瞬时受体电位阳离子通道亚家族V成员4）可能提供对潜在治疗效用的疾病机制的洞察。（例如，组织学，组学，流式细胞术或CyTOF）优化临床数据采集和分析方案，用于将来的HP-129 HP MRI在人类志愿者和患者研究中的发现探索临床前HP-129 HP MRI在其他器官部位（如肠道和大脑）中的组织屏障和转运评估

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