Download Towards Clinical Imaging of Inhibition of Mucus Degradation in

School of Medicine
PhD Project Application 2017
Towards Clinical Imaging of Inhibition of Mucus Degradation in
Respiratory Diseases
Section 1 – Project Details:
Maximum 800 words, using the following headings
Rationale: Airway mucus plugs, composed of mucin glycoproteins mixed with plasma
proteins, cause airway obstruction in patients with airways disease, such as cystic fibrosis and
bronchiectasis. Little is known about the effects of therapy on plug composition, airway
ventilation or clinical outcome. It has been shown that in healthy people mucus gel is degraded
by proteases with albumin inhibiting degradation. In airway disease however, the proteasedependent mucin digestion is inhibited and this may be caused by plasma proteins competing
with mucin substrate for proteolysis [1].
Mucin degradation is critical for plug clearance but in vivo methods monitoring this are lacking.
Mucin degradation changes the physical properties of the plug making it more liquid like rather
than solid which is reflected in the loss of entanglements between mucin molecules in the plug
and also in the reduction of the molecular weight of mucin. These changes in plug physical
properties may be captured by 23Na MRI methods and sodium MR signals have been shown
to reflect these changes in viscoelastic biofluids [2].
The feasibility of 23Na MRI in lungs has been demonstrated at 3T [3]. However, 23Na MRI has
never been used to characterise physical properties of airway mucus plugs in airways disease.
We propose to apply 23Na MRI for this purpose using 3T and 7T whole body scanners located
at Sir Peter Mansfield Imaging Centre (SPIMC), University of Nottingham. Currently there are
no good biomarkers for airway clearance. This project’s unique combination of mechanics and
imaging methodology, allied to clinical insight, could lead to identification of an early,
responsive, and valid biomarker for novel airway therapies (including monoclonal
antibodies/Ivacaftor) negating the need for long term clinical studies and leading to direct
patient benefit.
Aims and methodology: The project will combine (i) ex vivo testing of sputum samples, (ii) analysis of mechanical data and their computer modelling and (iii) - in vivo 23Na MRI of airway
mucus plugs in healthy volunteers and patients with airways disease.
(i)
Ex-vivo testing of sputum samples. Sputum samples will be collected from agedmatched groups of healthy volunteers (n=5), and patients with bronchiectasis (n=5)
and CF (n=5) pre and post intervention (carbocysteine/nebulised DNAse/ivacaftor).
The necessary ethical permits for samples acquisition exist via our biobank facility.
Testing of solid/liquid like behaviour of sputa samples will be performed using bulk
rheometry methods. The sputa samples will also be tested in the 9.4T NMR
rheometer by 23Na rheo-MRI methods to find mechano-imaging correlates.
(ii)
Analysis of mechanical data and mathematical modelling. The 23Na mechanoimaging measures will be correlated to the materials functions of sputum [4]. The
materials function values – storage (a measure of being solid like) and loss (a
measure of being liquid like) moduli will be validated by modulus measures
obtained with bulk rheology methods. Mathematical modelling will be used to
correlate mucous plug moduli deduced from bulk rheology and 23Na MRI
measures.
(iii)
In vivo 23Na MRI of airway mucus plugs. In vivo 23Na MRI will be performed at 3T
and 7T whole body MRI scanners located in SPMIC. All necessary coils and
ethical permits should be in place for the beginning of the funding period as 23Na
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School of Medicine
PhD Project Application 2017
MRI will use natural sodium concentration in the body and no additional sodium
injection is required.
Benefits and suitability as a PhD project:
Benefit 1. Mapping physical properties of sputum plugs in patients using in vivo
signals.
23
Na MRI
Benefit 2. Understanding the physical effects on mucous plugs of currently available mucolytic
therapies.
Benefit 3. Potential therapeutic application by targeting anti-mucous strategies to specific
airways disease phenotypes.
Benefit 4. Introduction of new MRI contrast (rheo-contrast) based on physical properties of
mucous plugs.
Suitability. This project is especially suited for a PhD course because of its novelty,
translational potential and interdisciplinary supervisory team containing clinicians and
scientists and the potential to deliver high quality research papers.
Key References: [1] Innes et al, American Journal of Respiratory and Critical Care Medicine,
180, 203-210 (2009); [2] Pavlovskaya et al, JPCL, 5(15): 2632-236 (2014); [3] Henzler et al,
ROFO (2012) doi: 10.1055/s-0031-12999277; [4] Mason, Rheologica Acta 39, 371-378 (2000)
Section 2 – Training Provision:
Maximum of 250 words. Please detail the training provision that will be made
available to the student.
The newly structured SPMIC, established through the recent MRC CRCTI award, brings
together Nottingham’s clinical and basic science imaging research to further facilitate
interdisciplinary dialogue and translation of novel MR techniques. Lung sodium imaging at 3T
and 7T has been made feasible by this infrastructure award and the studentship will work on
a new field of MR research and applications of 23Na imaging at high and ultra-high field in the
body. 23Na Rheo-MRI at 9.4T and bulk rheometry methods has been made available with the
current MRC –discovery funding (2016). The student will be trained and mentored in a variety
of skills from data acqusition to image processing with MRI and rheomtery and respiratory
physiology and pathology and in the developing of 23Na imaging.
The studentship will be supported by a strong link between the School of Medicine’s
Respiratory Research Group located at City Hospital and SPMIC. The Respiratory Research
Group has a full range of clinical and laboratory scientific resources. The student will get
training in computing and mathematical modelling under School of Mathematical Sciences
suprevision. Graham will provide training on multiscale modelling techniques. He has
extensive experience of using modelling to extract microscopic insight from bulk rheological
experiments. He achieves this by linking meso and molecular scaling modelling to continuum
rheological models that link to experiments. This multi-scale modelling approach was a key
factor in Graham receiving the 2011 Metzner award from the American Society of Rheology
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