Comparative molecular characterisation of inherited disease models of cancer and cardiovascular disease

Simpson, Siobhan (2017) Comparative molecular characterisation of inherited disease models of cancer and cardiovascular disease. PhD thesis, University of Nottingham.

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Abstract

Heart disease and cancer are leading causes of global non-communicable morbidity and mortality. There have been improvements in diagnosis, treatment, and survival for many heart diseases and cancers. There is, however, considerable potential for improvements in the prevention, diagnosis, and management of dilated cardiomyopathy (DCM) and osteosarcoma. There is currently no cure for DCM, and osteosarcoma survival rates have not improved in decades. New diagnostic tools and treatments are urgently needed for these diseases.

In this thesis, the overarching hypothesis is that diseases in the companion animal population represent good models of human disease, whilst also representing important veterinary clinical challenges. Specific hypotheses relating to the genetics of canine DCM and osteosarcoma were tested. Both diseases have high prevalence rates in certain breeds, in particular Irish Wolfhounds develop both DCM and osteosarcoma. As the same breeds are affected by both diseases it was proposed that a common mechanism might influence the development of both diseases in these dogs. To test whether this association was due to differences in androgen signalling the polyglutamine repeat tracts of the androgen receptor and NCOA3 genes were genotyped. Neither disease was associated with polyglutamine repeat tract length, but this does not exclude endocrine signalling as a common factor influencing canine DCM and osteosarcoma development. Genetic associations specific to each disease were also examined with a multigenic model of DCM developed in Doberman Pinschers and further tested in Irish Wolfhounds. This showed that multiple loci act together to influence DCM development and better predict disease than individual loci.

In addition to testing hypotheses relating to the genetics of DCM it was hypothesised that the fatty acid profiles of canine DCM patients would be different from other cardiac patients and non-cardiac patients. If differences can be identified it could lead to improved diagnosis and treatment, but also give indications as to which genes could be involved in disease pathology. Results presented in this thesis show that there is indeed a difference in fatty acid profiles between cardiac and non-cardiac patients, but that it is valve disease patients that appear different from all other patients. The transcriptome of osteosarcoma and non-malignant tissue was compared to identify novel biomarkers of disease with several interesting genes identified as differentially expressed in tumours compared to non-tumour tissue. Additional work is required to establish the nature of the disease process that is shared between canine DCM and osteosarcoma, and to identify additional genetic loci associated with disease.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Rutland, Catrin
Mongan, Nigel
Cobb, Malcolm
Subjects: R Medicine > RC Internal medicine
R Medicine > RC Internal medicine > RC 254 Neoplasms. Tumors. Oncology (including Cancer)
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Item ID: 40329
Depositing User: Simpson, Siobhan
Date Deposited: 07 Nov 2019 13:35
Last Modified: 06 May 2020 13:16
URI: http://eprints.nottingham.ac.uk/id/eprint/40329

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