Calcium-permeable channels and mechanobiology in health, disease and therapeutic development

Rationale

Despite improvements in medical care, cardiovascular disease remains the number one cause of death worldwide. The increasing problem of diabetes accelerates cardiovascular disease and makes its treatment more difficult. Physical activity protects, but we don’t know how.

We have sought ways to advance this field whenever possible without using animals – via cell and molecular biology lab studies, computational modelling/data analytics, and studies of human tissues – but mouse studies have been necessary. The central idea is that calcium-permeable channels, their mechanical sensitivities and associated mechanisms are pivotal and that targeting them with small-molecule modulators will lead to new therapeutic drugs.

Non-animal studies are expanding, but experiments involving animals are still required because of the complexity of integrated physiology and the need for preclinical animal studies to justify human trials. 

Plan of work

Sophisticated genetic manipulation will be used, in order to minimise animal suffering while still enabling meaningful important new data collection, as well as the administration of specific small-molecule modulators designed to mimic potential new drugs and independently validate the genetic findings.

Observation of the effects of gene change and small-molecule administration on cardiometabolic physiology of the mice will take place, using the most sophisticated, and where possible, non-invasive methodologies. 

Animal welfare

Substantial progress was made with replacement, reduction and refinement during our current licence and we will use new ways to achieve further improvements. It has been possible to cease most vascular injury and all tail cuff plethysmography, bone marrow transplantation and maximum tolerated dose studies, and the number of steps per animal has been halved. 

We are seeking major new research grants that would enable introduction of a cutting-edge remote pheno-typing system for cardiometabolic evaluation of mice in social groups with minimum human interference.

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