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Application of the new biology and transgenic techniques to cardiovascular research

Objective

This concerted action focused on the utilisation of state of the art molecular techniques to develop new animal models for hypertension and cardiovascular disease and thereby elucidate the causes of human primary hypertension. Our goal was to establish a unique programme to introduce discrete genetic changes into the genome of the rat, in order to understand not only the regulation of genes important to the function of the cardiovascular system, but also to gain insight into their involvement in hypertensive mechanisms.

Specifically, the purpose of this concerted action was to adapt transgenic technology to questions in cardiovascular research by the establishment of transgenic rats and to ensure the cooperation of European members who otherwise would have no access to such animals and who could offer laboratory expertise for detailed pathophysiological, hemodynamic, electrophysiological, endocrinological, pharmacological, environmental and behavioural investigations.

Specific aims

a) The establishment of transgenic rat methodology and introduction of the mouse Ren2 into the rat genome.
b) The preparation of new gene constructs by participating groups and the introduction of the constructs into the rat germline.
c) The distribution of new animal models to participants in TRANSGENEUR for detailed study utilising the specialised techniques available through combined efforts of the participants.
d) The establishment of a permanent cryogenic preservation facility for the storage of transgenic lines, especially those which are not required immediately by other laboratories is an important aim of this collaboration.
A central facility has been set up to develop and utilise transgenic technology in the rat and to make available new and more genetically defined animal models of hypertension to researchers in Europe. Several new and genetically defined hypertensive animal strains were generated by introduction of the mouse renin gene into the rat germline. The most interesting of the initial strains, TGRmRen2-27, has been successfully bred to homozygosity. This has been achieved by maintaining the animals on antihypertensive treatment, and means that the breeding and distribution of the strain is more efficient. Transgenic rat strains have also been constructed carrying human renin and human angiotensinogen genes. In addition, transgenic lines generated recently include hypertensive mice carrying the rat angiotensinogen gene. Collaborative studies are wide ranging and include the transfer of animals, gene constructs and plasmid vectors and methodology training.

A major success has been the active use of a cryogenic storage facility for transfer of frozen rat embryos. Test results on the first animals born from cryopreserved embryos and of other animals within the central facility showed them to be pathogen free. The preferred method of shipment of genetic lines is via frozen embryos and training in handling of embryos has been given.

The development of novel strains of a genetically hypertensive animal, whose genetic abnormality is defined, has given a new dimension to research within the field and provided a new experimental impetus in the fight against these diseases.
Cardiovascular morbidity and mortality accounts for about 50% of deaths in industrialised countries and is one of the major health issues of our time. 20% of the adult population has hypertension, the most important cause of cardiovascular mortality. Primary hypertension in man and spontaneously hypertensive rats is hereditary and it is believed that 4-6 major genes are involved. On this genetic basis environmental factors, lifestyle and diet can affect the phenotype. Although there are several animal models of hypertension, most notably the spontaneously hypertensive and stroke-prone spontaneously hypertensive rats (SHR-SP), to date the underlying genetic lesions in these animals have not been identified. Recent genetic mapping data show that a gene close to or coincident with the angiotensin converting enzyme gene is partially responsible for the hypertension in the SHR-SP strain. A formal demonstration will require gene transfer experiments of the type proposed in this application to be undertaken, and such experiments have been made possible in large part through the efforts of the TRANSGENEUR concerted action over the last two years. Large gaps remain in the understanding of the underlying mechanisms of hypertension and the identification of the genes involved. The preparation of new animal strains to test the contribution of specific genes has been shown to be a valid and exciting new avenue and several groups in the USA are initiating the construction of novel rat strains using in vivo gene transfer techniques. With the available expertise amongst the participants of this programme and the infrastructure support of the concerted action, European hypertension researchers have an unparalleled opportunity to utilise state of the art techniques to enhance their research into this disease.

Funding Scheme

CON - Coordination of research actions

Coordinator

University of Edinburgh
Address
King's Buildings West Mains Road
EH9 3JQ Edinburgh
United Kingdom