PTH/RAMP interactions a novel target for the treatment of osteoporosis

Project Details: Osteoporosis causes over 8.9 million fractures annually worldwide. This number will increase as population demographics shift with ever-advancing life expectancy. Over 20 million women are affected by osteoporosis, but increasing numbers of men are diagnosed with osteoporotic fractures. In the UK, the economic cost of osteoporotic fractures is £3.5 billion annually and this will rise to £5.5 billion by 2025. PTH (1-34) is the only clinical bone anabolic agent, but the effects of PTH on the skeleton can be anabolic or catabolic depending on the timing/duration of administration and it is not suitable for all patients.

We have novel data showing an accessory protein called a Receptor Activity Modifying Protein (RAMP) forms a functional heteromer with the PTH receptor. In the presence of a RAMP, PTH (1-34) and its related fragment stimulate different G-protein (Gαs, Gαi and Gαq) activation profiles. These changes result in altered downstream signalling that would either favour the anabolic or catabolic effects of PTH, depending on the combination of receptor, RAMP and ligand. These data show that by targeting a specific RAMP/PTH receptor combination we can specifically modulate “desirable” pathways leading to anabolic bone effects while avoiding deleterious effects catabolic bone effects that are associated with current PTH therapies.

The aim of this project is to test the hypothesis:

Receptor activity modifying proteins do not alter downstream consequences of PTH and related fragments in bone cells.

To test this hypothesis the student will use a variety of techniques including CRISPR, PCR, flow cytometry, cell signalling assays, cellular label free assays and Surface Plasmon Resonance. This work will be under taken in a recently established laboratory with cutting edge equipment. In collaboration with a biotech company, we are currently identifying peptides that selectively target the RAMP/PTH receptor interaction to elicit anabolic effects of PTH on bone. One of the objectives of this project would be to characterise these peptides and assess their suitability as potential therapeutic agents.