Biophysical and Structural Characterisation of Genetic Variants of Receptor Activator of NF-B – understanding their role in cancer.

Interested individuals must follow Steps 1, 2 and 3 at this link on how to apply
http://www.ed.ac.uk/biology/prospective-students/postgraduate/pgr/how-to-apply

Receptor activator of nuclear factor-B (RANK) performs a key role in the regulation of bone metabolism, mammary gland and lymph node development, thermogenesis and T-cell growth. This project aims to uncover the molecular basis of the functions of genetic variants of RANK in health and disease.

RANK is constitutively expressed in many cells and tissues, including osteoclasts and mammary gland epithelial cells, skeletal muscle, thymus, prostate and liver. Its cognate ligand, RANKL, is expressed by osteoblasts, stromal cells and T cells. Both RANK and RANKL are expressed in some cancer cells, including breast and prostate cancers. Several alternatively-spliced variants of RANK have been identified which produce protein isoforms with distinct functions that have been associated with breast cancers.

This project aims to characterise the effects of alternative splicing on the 3D structures and interactions of these protein isoforms. You will employ a biophysical and structural approach to study the genetic variants of human RANK, and will investigate specific intermolecular interactions at the domain level in order to fully understand the role of RANK in signal transduction. Structure-guided, site-directed mutagenesis will be employed to confirm the functional importance of specific residues and interactions revealed by the work. In parallel, cell assays will be performed to assess the functional consequences of genetic variants.

Early in the project, training will be in molecular biology and recombinant protein technology, in order to over-express and purify recombinant proteins from various expression systems. The student will also be trained and gain invaluable experience in a range of biophysical techniques, including NMR and/or crystallography, mass spectrometry, light scattering, circular dichroism and isothermal titration calorimetry. Further training will develop skills with mammalian cell culture and assays.

The student will have access to all the PhD training programmes, including journal clubs, method clubs, scientific writing skills and presentation skills.

This project will be jointly supervised by Dr Janice Bramham, in the Institute of Quantitative Biology, Biochemistry and Biotechnology (http://www.ed.ac.uk/biology/people/profile/jbramham), and Professor Stuart Ralston, in the Institution for Genomic and Experimental Medicine (http://www.cgem.ed.ac.uk/research/people/stuart-ralston).