Skip to main content

Elucidation of the molecular and functional basis of disease phenotypes in the rat model

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.

Call for proposal

ERC-2010-AdG_20100317
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

THE UNIVERSITY OF EDINBURGH
Address
Old College, South Bridge
EH8 9YL Edinburgh
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 253 482,71
Principal investigator
Timothy Aitman (Prof.)
Administrative Contact
Alan Kennedy (Mr.)

Beneficiaries (2)

THE UNIVERSITY OF EDINBURGH
United Kingdom
EU contribution
€ 1 253 482,71
Address
Old College, South Bridge
EH8 9YL Edinburgh
Activity type
Higher or Secondary Education Establishments
Principal investigator
Timothy Aitman (Prof.)
Administrative Contact
Alan Kennedy (Mr.)
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
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Scott Wheatley (Mr.)