|dc.contributor.author||Shephard, Rhian Elise||-|
|dc.description.abstract||Hypertrophic cardiomyopathy (HCM) is an inherited heart disease and no pharmacological therapies have been shown to prevent or cause regression of this disease in humans. HCM is caused by mutations in sarcomere-encoding genes, and up to 5% of HCM patients have multiple disease-causing mutations, correlating with a more severe phenotype.
This thesis investigated losartan as a preventative therapy in the TnI-203/MHC-403 mouse model of severe, multiple-mutation HCM. Treatment significantly increased survival, improved cardiac function, restored heart morphology, decreased cardiac fibrosis, and reduced the expression of pro-fibrotic and pro-hypertrophic molecules in ventricular tissue. Subsequently, expression profiling was carried out to determine miRNAs effected by losartan therapy in the diseased heart, in order to identify potential therapeutic targets. Two miRNAs were up-regulated (miR-203, miR-30c) and four miRNAs were down-regulated (miR-21, miR-214, miR-31, miR-199a-3p) with this treatment.
The final study sought to develop lentiviral-mediated gene transfer tools in order to create a cell line for screening pharmacological- or miRNA- therapies. Lentiviral particles were successfully engineered, and preliminary results indicated the expression of TNNI3-G203S in cardiomyocytes caused cellular hypertrophy, a hallmark characteristic of this disease.
In conclusion, losartan treatment improved disease in the TnI-203/MHC-403 model, miRNAs altered with this treatment were identified, and gene transfer tools for the introduction of HCM-causing mutations were successfully engineered.||en_AU|
|dc.publisher||University of Sydney||en_AU|
|dc.publisher||Sydney Medical School||en_AU|
|dc.publisher||Central Clinical School||en_AU|
|dc.title||Severe hypertrophic cardiomyopathy and heart failure caused by multiple mutations: from molecular pathogenesis to pharmacological intervention||en_AU|
|dc.type.pubtype||Doctor of Philosophy Ph.D.||en_AU|
|Appears in Collections:||Sydney Digital Theses (Open Access)|