Control of alternative pre-mRNA splicing in the generation of inflammation and pain

The control of alternative pre-mRNA splicing in the generation of inflammation and pain.
Supervisors: Lucy Donaldson and David Walsh.
Pain is a fundamental sensation that serves to alert the body to potential or actual damage, and to invoke protective responses to prevent further damage. Damage to tissues stimulates a complex series of events, in multiple cell types, that are part of the repair process. In some circumstances cellular changes do not result in repair, but instead lead to continued damage and, pain. Inflammation contributes to pain and tissue damage in arthritis across mammalian species, so controlling inflammation can have benefit for both animal and human welfare.
Expression of different proteins by alternative RNA splicing is increasingly recognised as a key pathogenetic mechanism, although its contribution and control in inflammation and pain remains to be explored. We have evidence that in fibroblast-like synoviocytes, the cells that line the joint space, fundamental inflammatory responses such as immune cell adherence are controlled by alternative pre-mRNA splicing, particularly of the growth factor family vascular endothelial growth factor (VEGF).
This project will combine studies in animals and human tissue to interrogate the control of alternative pre-mRNA splicing in pain generation. The focus will be on the alternative splicing controls of VEGF but other targets might also be explored. You will test the hypothesis that changes in alternative splicing actively contribute to inflammation and pain by: 1. localising key components of the alternative splicing machinery in inflamed/damaged human synovial tissue to determine cell types in which this mechanism is active; 2. using isolated synoviocytes to model arthritic inflammation in vitro, to determine mechanisms through which alternative splicing is regulated under these conditions, and test novel drugs that could alter these processes, and 3. Using experimental animals to test effects of alternative splicing on arthritis pain mechanisms.
The project will be fully supported by the expertise and biorepositories within the Arthritis Research UK Pain Centre at the University of Nottingham (http://www.nottingham.ac.uk/paincentre).