Download Aberrant mRNA splicing patterns and nonsense

Aberrant mRNA splicing patterns and nonsense-­‐mediated decay caused by mutant DMD gene. Project Code:PHBM2091016 Project detail: The Molecular Medicine Group, School of Pharmacy and Biomedical Sciences is recruiting highly talented and motivated students with excellent qualifications for a PhD in biomedicine. The current call offers fully-­‐funded PhD position supported for a period of 3-­‐4 years to carry out research on “The secondary abnormalities of DMD gene mutations”. The DMD is the largest human gene, with 79 exons in a variety of alternatively-­‐spliced transcripts, which expression is tightly controlled by 7 promoters. DMD mutations cause a lethal Duchenne muscular dystrophy. However, there is increasing evidence, also from our laboratory, that in addition to the well-­‐known effects on muscle fibres, DMD impacts on a whole spectrum of functions in myogenic and also in non-­‐muscle cells, e.g. causes pathogenic purinergic abnormality, altered energy metabolism, calcium entry, cell proliferation and differentiation and synaptic organisation leading to cognitive impairments. DMD also controls asymmetric division of muscle stem cells and is a tumour suppressor gene. The aim of this project is to establish how DMD gene mutations may cause such a variety of abnormalities in a number of functionally discordant cell types. This will be done using the mdx mouse model, where a single point mutation in the DMD gene produces well characterized phenotypic changes. We have performed NGS comparison of mutant and control transcriptomes and have identified novel and unexpected secondary alterations resulting from DMD mutations. This project, as a part of larger research programme aiming at understanding the impact of DMD mutations on global gene expression and function, will study coding and non-­‐coding differentially expressed/spliced/decayed RNAs in normal and dystrophic cells and will determine the underlying regulatory abnormalities. It will direct future strategies aimed at finding a treatment for the incurable Duchenne muscular dystrophy. Successful candidates will join an established Molecular Medicine research group with a track record in identifying novel approaches in DMD research (Autophagy, 2105; PLOS Medicine, 2015). This multidisciplinary project will span a broad range of techniques including, but not limited to: molecular biology, biochemistry and bioinformatics. Previous experience in one or more of these areas would be advantageous, although full training in all relevant techniques will be offered. In addition, the PGR will benefit from a well-­‐established and vibrant international scientific environment, the state of the art infrastructure, research seminars, specialized scientific training as well as from the complementary skills and career development training modules of an integrated Graduate School programme. Supervisors on this project with be Professor Darek Gorecki and Dr Quang Si, from the School of Pharmacy and Biomedical Sciences. Informal enquiries may be made to Professor Darek Gorecki -­‐ ([email protected]).