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Deep Phenotyping of Crohn’s Patients using a Precision Imaging Approach to Identify Drivers and Stratify Risk of Wasting and Myosteatosis

Project Description

Up to 75% of hospitalized Crohn’s disease (CD) patients are malnourished and as many as 50% are in negative nitrogen balance(1), but variations in muscle mass and quality in this group is poorly characterised as are the drivers of such pathophysiology. Importantly however these variables are likely to impact significantly upon patient quality of life and the trajectory of decline with age. The acute inflammatory response as measured through C-reactive protein (CRP) is high in wasted CD patients (2), furthermore 41.6% of these patients require surgery(3) indicating that a chronic inflammatory insult may be linked to muscle mass depletion. To this effect, 60% of adult CD patients still have clinical evidence of low muscle mass even when in clinical remission (4) indicating the poorly reversible nature of this chronic phenomenon (see graphic). Maintaining skeletal muscle mass is a tightly regulated process controlled by the fine balance between muscle protein synthesis and muscle protein breakdown, and adult patients with active CD show a significant decrease in expression of hypertrophy signalling with no apparent change in the expression of atrophy signalling(5). This latter observation is in keeping with the concept of ‘anabolic resistance’, i.e. the blunting of the stimulatory effect of protein nutrition and/or exercise on muscle protein synthesis, which is thought to be a main driver formuscle mass loss in ageing and inflammatory states, such as critical illness, and possibly CD. In parallel with muscle mass loss is the development of myosteatosis, i.e. the accumulation of intra and extramyocellular lipid. It is not known whether this is directly linked to the concurrent loss of muscle mass in ageing and chronic disease progression or simply reflects reduced physical activity levels, but it is known to be associated with exacerbated anabolic resistance of muscle protein synthesis(6). Published research using stable isotope approaches to directly measure muscle protein turnover has shown negative protein balance in children(7), but not adults(8), with active CD. Our pilot data have confirmed negative skeletal muscle protein balance in children with CD(9). We hypothesise therefore that a chronic inflammatory burden in relatively young patients, rather than an acute inflammatory insult in adulthood, will be pivotal in the accentuation of muscle loss and myosteatosis in CD.
Accurate quantification of whole-body muscle mass and intramyocellular vs extra-myocellular lipid content in people has to date limited research progression. However, these methodologies are currently being validated at UoN against robust stable-isotope tracer and insulin clamp methodologies in healthy people by the applicants. We propose that the student should utilise these powerful imaging approaches to deeply phenotype CD patients to understand better the extent of muscle wasting and myosteatosis in these patients and hopefully stratify patients in terms of burden so as to gain greater insight of the drivers of pathophysiology in this patient group. This will also highlight those patients most likely to benefit from countermeasure intervention.
The student will also investigate some potential novel markers of muscle function including magnetization transfer, APT-CEST (related to mobile amide groups) and glycogen-CEST. These are currently being evaluated at 7T but have been used in a few studies in the liver at 3T, and will be piloted in this studentship. The student will be involved in setting up these measurements based on a spectroscopy readout for increased sensitivity.
The student would recruit young (16-25 years, n=20) and older (55-75 years, n=20) male CD patient cohorts with newly diagnosed (5 years)(10). CDactivity will be defined as a high CRP (>5g/dl) or a high faecal calprotectin (>250ug/g)(11) or as indicated through endoscopy or cross sectional imaging within 3 months of recruitment. Findings in the CD cohorts will be compared to an age-, BMI and gender-matched healthy volunteer cohort (n=10). CD patients will be recruited from the Inflammatory Bowel Disease Clinics at Nottingham University Hospitals under the supervision of Dr G Moran.
Please follow link to full project description.

Funding Notes

Deadline for applications is 25 February 2019, with interviews for applicants to take place between 4 and 8 March 2019
Applicants for the Precision Imaging PhD programme should have at least a 2:1 degree, or equivalent, in a project-relevant discipline. Funding is only available for UK and EU students.

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