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Hypertrophic cardiomyopathy (HCM), the most common cardiac disease in humans and cats, occurs spontaneously in 15% of domestic cats and may cause heart failure, cardioembolic complication or death. Sudden onset life-threatening clinical signs cause distress to cat owners and frustration to veterinary surgeons. Despite the severity and prevalence of HCM, treatment solutions are currently limited. Genomic studies could provide insights into the underlying molecular mechanisms resulting in HCM and lead to the development of targeted therapeutics and diagnostics, as in humans.
There is evidence that the disease is heritable, and a genetic association with an HCM phenotype has already been identified in the Maine coon and Ragdoll breeds. Previous studies in domestic cats used a candidate gene approach based on knowledge from human studies. These studies identified two HCM-associated mutations in the myosin binding protein C3 (MYBPC3) gene. However, the candidate gene approach has failed to identify any further causative mutations.
This project is aimed at investigating the genetic architecture and the underlying molecular mechanism of HCM susceptibility in cats. Our hypothesis is that HCM is a complex disease of polygenic inheritance controlled by several variants in both protein-coding genes and regulatory elements. Therefore, in the proposed study we will use genome-wide approaches to detect loci and genomic regions affecting HCM occurrence using meticulously phenotyped cats from 2 pedigree breeds.
With access to myocardial tissues and DNA from cats with HCM and controls, the student will perform genome-wide association studies, next generation sequencing and transcriptomic profiling and assess the results in conjunction with pre-existing and collated extensive phenotypic and epidemiological data.
The student will be trained in cutting-edge genetic and bioinformatic technologies, and relevant wet lab techniques to explore DNA-array, exome- and RNA- sequencing data to identify genetic markers, causative genes and gene networks underlying feline HCM. This project is in collaboration with Zoetis, one of the world leading companies in animal health. The student will interact with experts in drug discovery while he/she will undertake a placement in the R&D site in Belgium working within a team where the focus will be on preclinical pharmaceutical development based on the findings of the project. There will also be opportunity to collaborate directly with leading international veterinary and human research teams working on HCM projects during the course of the PhD.
Our findings might provide the means to control the disease, via genetic testing and selective breeding programmes, but they could also help identify new therapeutic targets for cats. HCM is strikingly similar in humans and cats; deciphering feline HCM genetics could provide new insights into the human disease.