Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Pathology and Laboratory Medicine

Collaborative Specialization

Molecular Imaging

Supervisor

Dr. Savita Dhanvantari

Affiliation

Imaging Program, Lawson Health Research Institute, London ON

2nd Supervisor

Dr. Lisa Hoffman

Affiliation

Imaging Program, Lawson Health Research Institute, London ON

Abstract

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease of skeletal and myocardial degeneration. Eventually, dilated cardiomyopathy develops from ischemia, inflammation and fibrosis. Due to the high mortality rate, there is an emerging need to diagnose DMD cardiomyopathy at early stages. Currently, DMD cardiomyopathy is diagnosed by imaging investigations and detection of circulating biomarkers. However, current imaging strategies detect functional and morphological changes but fall short in detecting molecular changes that underlie this disease. Circulating biomarkers provide information on the molecular level, but they are not cardiac-specific. Therefore, there is an emerging need for a biomarker that is endogenous to cardiac tissues. The growth hormone secretagogue receptor (GHSR) and its ligand, ghrelin are produced by both cardiomyocytes and vascular endothelial cells and could be an indicator of DMD cardiomyopathy. The work described in this thesis sought to characterize GHSR as a cardiac-localized biomarker in DMD cardiomyopathy. Histopathology and confocal imaging using a novel fluorescent ghrelin analog, Cy5-ghrelin(1-19), were used to investigate changes in cardiac tissue architecture and GHSR and inflammatory markers in the mdx:utrn-/- mouse model of DMD. My studies show that GHSR is elevated in mdx:utrn-/- myocardial tissues and correlate strongly with the macrophage marker F4-80 and the pro-inflammatory cytokine IL-6. Interestingly, I also show that both ghrelin and des-acyl ghrelin bind to sites in large cardiac vessels of mdx:utrn-/- which might be an indicator of vascular inflammation. Finally, my project shows the first report of GHSR in cardiac macrophages. In summary, my work suggests that, in dilated cardiomyopathy, elevations in GHSR correlate with the inflammatory phenotype as mediated by both the myocardium and macrophages.

Summary for Lay Audience

Heart disease is the leading cause of death in Canada. It is usually diagnosed by imaging, such as ultrasound. However, this kind of imaging can miss small changes in the heart that lead to heart disease. My work has addressed this issue by identifying a protein located in the heart muscle that may indicate the onset of heart disease. I showed that this protein, called GHSR, is increased in the heart in a mouse model of heart disease, along with the degree of inflammation in the heart. My research has shown that there may be more sensitive ways of detecting heart disease, so that it may be diagnosed at earlier stages.

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