Determining the role of elevated ghrelin in Prader-Willi Syndrome
Applicants (UK, EU and international) capable of self-funding or with scholarship are welcome to apply.
Principle supervisor: Dr Timothy Wells (BIOSI, Cardiff University)
Second supervisor: Dr Anthony Isles (Behavioural Genetics, MEDIC, Cardiff University)
Collaborator: Prof Yuxiang Sun (Baylor College of Medicine, Houston, Texas)
This project will test the hypothesis that:
The metabolic symptoms of Prader-Willi Syndrome are due to chronically elevated circulating ghrelin Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by disruption of an imprinted gene cluster on human chromosome 15q11-q13 and is clinically characterized by severe hypotonia at birth and a failure to thrive in infancy. On emerging from infancy, PWS patients show mild learning disabilities, reduced skeletal growth and impaired satiety responses, which, when combined with elevated circulating ghrelin and an obsession with food, results in obesity.
We have demonstrated that many of these symptoms are recapitulated in a novel PWS mouse model (PWS-IC). These mice display hyperphagia, exaggerated food hoarding and alterations in reactivity to palatable foodstuffs, and motivation by food rewards in appetite-reinforced cognitive tasks (Human Molecular Genetics 18:2140 (2009); European Journal of Neuroscience 31:156 (2010)). In a new collaboration, we have generated unpublished data showing that PWS-IC mice also display reduced skeletal growth and reduced fat mass, combined with lower body temperature and increased thermogenesis. These characteristics accompany a 3-fold elevation in circulating ghrelin.
Since ghrelin is a powerful orexigenic and obesogenic hormone, you will determine which of the phenotypic characteristics of the PWS-IC model are dependent upon elevated ghrelin by generating and assessing a ghrelin-null x PWC-IC mouse model. You will:
- Cross ghrelin-null mice with PWS-IC mice to generate a stable ghrelin-null x PWS-IC mouse line.
- Use and automated feeding station to assess the disturbances of feeding patterns.
- Use metabolic chambers to assess hoarding behaviour and the metabolic effects of increased dietary fat and palatability.
- Use thermal imaging to establish the profile of thermogenesis.
Thus, you will establish the role of elevated ghrelin signalling in Prader-Willi Syndrome and describe a number of novel actions of this hormone.