Author's School

School of Engineering & Applied Science

Author's Department/Program

Biomedical Engineering

Language

English (en)

Date of Award

Spring 2-17-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Samuel A. Wickline

Abstract

Cardiac dysfunction is a primary cause of mortality in Duchenne Muscular Dystrophy (DMD), potentially related to elevated cytosolic calcium. However, the regional versus global functional consequences of cellular calcium mishandling have not been defined in the whole heart. Here, we elucidate, for the first time, loci- and age-dependencies between calcium mishandling and myocardial sheet function as a manifestation of dystrophin-deficient cardiomyopathy. We also map calcium transients to illustrate the regional dependence of ion flux disturbances in the dystrophin-deficient (mdx) mouse heart. Furthermore, we elucidate abnormalities in autophagic processes that can be corrected with nanoparticle therapeutics delivering rapamycin to heart tissues to improve ventricular function in affected older mice with incipient cardiomyopathy. We conclude that the rapid reversibility of functional defects by reducing cytosolic calcium or by impacting impaired autophagy points to the significance of regional mechanical factors in the progression of the disease.

Comments

Permanent URL: http://dx.doi.org/10.7936/K7XS5SDB

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