The Role of MRAP2 in Primary Cilia–Mediated Regulation of Energy Homeostasis

Childhood obesity is on the rise: 22.1% of UK 10–11-year-olds are now obese. Although food and living environment play an important role here, our genetic blueprints can put us at increased risk of becoming overweight and developing complications such as type-2 diabetes. There are many proteins and molecules involved in controlling our appetite, energy balance and blood sugar levels. MRAP2 seems to be a very important protein that determines weight. People with loss of MRAP2 have early onset obesity, high blood pressure and high blood sugar. We know that the protein interacts with a number of receptors, which are proteins on cells and we are learning how MRAP2 makes these receptors move to certain places in the cell such as the cilia. The cilia is hair-like structures that stick out from the surface of most cells in the body and is important in sensing signals like hormones and nutrients. The cilia on certain nerve cells in the brain can dictate the food intake and calories expended. We now know that MRAP2 can move a particular receptor to the cilia but how it does this and the full extent of its ability to move other proteins and receptors is not known. The aim of this project is to study how MRAP2 is able to move receptors to primary cilia and the consequences of this. Year 1, we will determine location and consequence of cilia MRAP2/receptor interaction (months 1-12). MRAP2/receptor cilia localisation using advanced microscopy in months 1-8 and consequences of this interaction using state-of-the-art reporter assays in months 6-12. Year 2 will study the effects of human MRAP2 loss-of-function mutations (months 12-24), year 3/4 to define in-vivo outcomes of MRAP2 enabled cilia receptor localisation (months 24-46), with dedicated time for thesis writing/submission and a range of personal developmental opportunities.