The effect of cholesterol on satiety
There has been a poor record of success in the pharmacological treatment of obesity. The cholecystokinin 1 receptor (CCK1R) regulates some gastrointestinal functions and also performs an anorexigenic role as part of the gut-brain axis. This appetite supressing role makes CCK1R a good target as an anti-obesity therapeutic. In spite of this, an orally available small molecule CCK1R agonist failed to perform better than diet and exercise in a clinical trial on overweight and obese patients.
We know that CCK1R signalling is modulated by membrane cholesterol. Paradoxically high cholesterol increases CCK1R agonist affinity whilst simultaneously decreasing response potency (efficacy). Thus, high membrane cholesterol is interfering with coupling of the receptor (CCK1R) to its transducer (G⍺q).
The project will involve the investigation of the biophysical basis of CCK1R:G⍺q in the presence of different levels of membrane cholesterol along with investigation of a cholesterol insensitive mutant of the CCK1R. This project will form part of an ongoing collaboration with Larry Miller M.D. at the Mayo clinic in Arizona.
Students would engage in three lab rotations in Year 1 prior to selection of a project and supervisory team.