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Candida Desjardins, PhD
Candida Desjardins, PhD
MSTP (MD/PhD Program)
March 4, 2015 noon
School of Medicine E501

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Committee: (Advisor)
Early Detection of Physiologic and Functional Changes of Common Structural Protein Mutations Underlying Human Diseases by MRI

The most common genetic disorders of skeletal and cardiac muscle result from mutations in structural proteins essential for normal tissue function. The ability to identify tissue dysfunction prior to the onset of overt clinical symptoms will provide better insight of physiology and treatment of pathology. Hypertrophic cardiomyopathy (HCM) is the single most common genetic disorder of the heart, resulting from mutations in sarcomeric proteins, and manifesting as sudden death or progressive heart failure. Characterization of early cardiac phenotypes and improved screening measures in HCM may reduce morbidity and mortality. Likewise, Duchenne Muscular Dystrophy (DMD) is an X-linked progressive, invariably fatal disease of skeletal and cardiac muscle resulting from mutations in dystrophin, one of the largest genes in the genome. One of the largest causes of mortality in this cohort is dilated cardiomyopathy. There is also a need to identify extra-cardiac sequelae of dystrophin mutations as new therapies may dramatically improve the life expectancy of patients with DMD. Indeed, dystrophin is also necessary to maintain the blood-brain barrier and cerebrovascular disease is case-reportable in DMD patients. The goal of this work is to explore the physiologic consequences of aberrant structural proteins using in vivo magnetic resonance imaging (MRI). In particular, MRI techniques were used to detect early pathologic changes in cardiovascular and vascular function prior to the manifestation of overt symptoms in mouse models of HCM and DMD, respectively. Here, we demonstrate that in a mouse model of HCM, displacement encoding with stimulated echoes (DENSE) MRI detects left ventricle mechanical dysfunction antecedent of pathologic hypertrophy. We also demonstrate that velocity vector imaging echocardiography is comparable to DENSE MRI in identifying mechanical dysfunction in cardiomyopathy. Further, we developed an arterial spin labeling-fast imaging with steady-state free precession (ASL-FISP) MRI method as a means to measure cerebral perfusion. Finally, in a mouse model of muscular dystrophy, ASL detected decreased cerebral perfusion in setting of increased angiogenesis. Taken together, we demonstrate that the development of new imaging technologies not only might allow earlier diagnosis and thus more timely intervention, but also may facilitate identification of subtle and clinically relevant phenotypes in important disease states.