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

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