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Bill Colledge's previous research projects

Cystic fibrosis

My laboratory has generated two different mouse models of cystic fibrosis (CF), CF null and ΔF508, and used these to perform successful gene therapy in vivo. These mice were vital for the preclinical testing of gene delivery reagents that allowed us to conduct two Phase I human clinical trials for CF. Breeding pairs of these mice are available to the CF research community as part of the EuroCareCF Coordinate Action group funded by the European Commission. My group has continued to develop innovative strategies to improve the efficiency of gene delivery including using chemical adjuvants, peptides and protein transduction domains to enhance gene expression.

We have also developed transgenic mouse lines to facilitate further research in this field such as a line with a tetracycline inducible CFTR gene and another with a mutated LacZ reporter gene to identify rare gene repair events at genomic loci in vivo.

Related publications

Buckley SM, Waddington S, Jezzard S, Bergau A, Themis M, MacVinish L, Cuthbert A, Colledge WH, Coutelle C, (2008), Intra-amniotic delivery of CFTR-expressing adenovirus does not reverse cystic fibrosis phenotype in inbred CFTR-knockout mice, Mol Ther, 16:819-824

Pier GB, Grout M, Zaidi T, Melulenl G, Mueschenborn SS, Banting G, Ratcliff R, Evans MJ, Colledge WH, (1998), Salmonella typhi uses CFTR to enter intestinal epithelial cells, Nature, 393:79-82

Hyde SC, Gill DR, Higgins CF, Trezise AEO, MacVinish LJ, Cuthbert AW, Ratcliff R, Evans MJ, Colledge WH, (1993), Correction of the ion transport defect in cystic fibrosis transgenic mice by gene therapy, Nature, 362:250-254

Colledge WH, Abella BS, Southern KW, Ratcliff RA, Jiang C, Chen SH, MacVinish LJ, Anderson JR, Cuthbert AW, Evans MJ, (1995), Generation and characterisation of a ΔF508 cystic fibrosis mouse model, Nature Genet, 10:445-452

Ratcliff R, Evans MJ, Cuthbert A, MacVinish L, Foster D, Anderson JR, Colledge WH, (1993), Production of a severe cystic fibrosis mutation in mice, Nature Genet, 4:35-41

 

Cardiac physiology

My group has also generated several transgenic lines with mutations in cardiac-specific ion channels to study the mechanisms and risk factors associated with life threatening cardiac arrhythmias. The mutations that we introduce into these ion channels are all associated with human cardiac dysfunction so that the mice can be used to directly model and understand human disease. We have introduced different mutations into the cardiac sodium channel gene Scn5a to model two different human syndromes, LQT3 and Brugada. These mice have slowed atrioventricular conduction and ventricular tachycardia.

Related publications

Stokoe KS, Balasubramaniam R, Goddard CA, Colledge WH, Grace AA, Huang CL, (2007), Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/– murine hearts modelling the Brugada syndrome, J Physiol, 581:255-275

Thomas G, Gurung IS, Killeen MJ, Hakim P, Goddard CA, Mahaut-Smith MP, Colledge WH, Grace AA, Huang CL, (2007), Effects of L-type Ca2+ channel antagonism on ventricular arrhythmogenesis in ΔKPQ Scn5a (long QT3) murine hearts, J Physiol, 578:85-97

Stokoe KS, Thomas G, Goddard CA, Colledge WH, Grace AA, Huang CL, (2007), Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/– murine hearts modelling long QT3 syndrome, J Physiol, 578:69-84

Head CE, Balasubramaniam R, Thomas G, Goddard CA, Lei M, Colledge WH, Grace AA, Huang CL-H, (2005), Paced electrogram fractionation analysis of arrhythmogenic tendency in ΔKPQ Scn5a Mice, J Cardiovasc Electrophysiology, 16:1-12

Royer A, van Veen TA, Le Bouter S, Marionneau C, Griol-Charhbili V, Leoni AL, Steenman M, van Rijen HV, Demolombe S, Goddard CA, Richer C, Escoubet B, Jarry-Guichard T, Colledge WH, Gros D, de Bakker JM, Grace AA, Escande D,  Charpentier F, (2005), Mouse model of SCN5A-linked hereditary Lenegre's disease. Age-related conduction slowing and myocardial fibrosis, Circulation, 111:1738-1746

Papadatos GA, Wallerstein PMR, Head CEG, Ratcliff R, Brady PA, Benndorf K, Saumarex RC, Trezise AEO, Huang CL-H, Vandenberg JI, Colledge WH, Grace AA, (2002), Slowed conduction and venticular tachycardia following targeted disruption of the cardiac sodium channel gene Scn5a, Proc Natl Acad Sci USA, 99:6216-6221

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