Objective Recent genetic studies have identified hundreds of susceptibility genes for common human diseases but genetic effects are small and identifying underlying mechanisms remains challenging. Rodent models offer significant advantages for analysis of disease phenotypes. Advances in genome resources and gene targeting have increased the attractiveness of the rat model for genetic studies but progress has been hampered by absence of relevant rat genome sequences.We recently sequenced the genome of the spontaneously hypertensive rat (SHR) and will shortly have completed the Wistar Kyoto (WKY) rat sequence. The SHR genome contains over 750 genes that are completely or partly deleted, or have a frameshift in their open reading frame. These sequence variants, along with variants controlling dysregulated gene expression that we characterised previously, most likely include the major determinants of SHR cardiovascular and metabolic disease phenotypes.We shall determine the functional consequences of these variants by creating and phenotyping transgenic and knockout rats on the SHR and WKY genetic backgrounds, using transposon-mediated transgenesis and zinc-finger nuclease-mediated gene deletion recently shown to be highly efficient in rats. Genes will be prioritised for study by statistical and informatic analyses using our extensive physiological, gene expression and linkage data in these rat strains, and by comparative analysis with data from human genome-wide association studies. Confirmed rat disease genes will be tested for conserved functions in humans.These proposals provide a systematic route to elucidating the molecular and functional basis of disease phenotypes in SHR and WKY rats, and for translating these findings to advance understanding of common human diseases. Fields of science natural sciencesbiological sciencesgeneticsgenomes Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-AG-LS2 - ERC Advanced Grant - Genetics, Genomics, Bioinformatics and Systems Biology Call for proposal ERC-2010-AdG_20100317 See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Coordinator THE UNIVERSITY OF EDINBURGH Address Old college, south bridge EH8 9YL Edinburgh United Kingdom See on map Region Scotland Eastern Scotland Edinburgh Activity type Higher or Secondary Education Establishments Principal investigator Timothy Aitman (Prof.) Administrative Contact Alan Kennedy (Mr.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution No data Beneficiaries (2) Sort alphabetically Sort by EU Contribution Expand all Collapse all THE UNIVERSITY OF EDINBURGH United Kingdom EU contribution € 1 253 482,71 Address Old college, south bridge EH8 9YL Edinburgh See on map Region Scotland Eastern Scotland Edinburgh Activity type Higher or Secondary Education Establishments Principal investigator Timothy Aitman (Prof.) Administrative Contact Alan Kennedy (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Other funding No data IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE Participation ended United Kingdom EU contribution € 1 222 625,51 Address South kensington campus exhibition road SW7 2AZ London See on map Region London Inner London — West Westminster Activity type Higher or Secondary Education Establishments Administrative Contact Scott Wheatley (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Other funding No data
