The pharmacological relevance of pro-peptide of GDNF family members

Theme: Bioscience for Health

Type 2 Diabetes and metabolic diseases more generally together with cardiovascular diseases affect increasing numbers of people. There is interest in regenerative approaches for both pancreaticbeta-cells and cardiomyocytes. TGFbfamily proteins play an important part in cell development and differentiation as well as in disease and BMP2 has been successfully developed and is marketed as a regenerative factor for bone growth. GDNF subfamily of growth factors are normally used as neurotrophic factors, but neurturin in particular has been shown to have beneficial effect on diabetic animals, lowering their glucose levels in insulin dependent manner. While the mechanism for this is unknown, the use of neurturin as therapeutic agent is compromised by its poor pharmacodynamic properties and limited tissue distribution. As neurturin, like all GDNF-like proteins, is synthesised as larger precursors. We have recently shown how activin A has very different properties when complexed with its pro-peptide. We hypothesise that the precursor forms of neurturin are similarly different from the mature protein so far used in the assessment of therapeutic potential. The aim of this project is to produce pre-cursor forms of neurturin and analyse its biochemical, biological and structural activities. At the same time we will analyse the effect of the pro-peptide on the bioavailability and tissue distribution of the growth factor, with an aim of developing more effective therapeutic agents.