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"Mediating Duchenne Muscular Dystrophy Skeletal and Cardiac Muscle Pathology Through Membrane Protein Modulation and Chimeric Modeling"

J. Patrick Gonzalez
Cell Biology and Molecular Medicine Program
B.S. 2010, Syracuse University, NY

Thesis Advisor: Diego Fraidenraich, Ph.D.
Assistant Professor
Department of Cell Biology and Molecular Medicine


Monday, September 14, 2015
3:00 P.M., MSB G609


Duchenne muscular dystrophy (DMD) is a neuromuscular degenerative disease caused by an inherited or spontaneous X chromosome mutation that leads to the absence of the critical protein dystrophin. DMD is considered the most common and most lethal form of muscular dystrophy, affecting nearly 1 in every 3500 newborn males. In skeletal and cardiac muscles, dystrophin is responsible for forming a structural link between the actin cytoskeleton and the sarcolemma, stabilizing the dystrophin glycoprotein complex (DGC). In DMD, the absence of dystrophin leads to the breakdown of this complex and the downregulation of DGC protein levels. This results in the significant impairment of muscle development and function, as well as the susceptibility to stress-induced damage. Patients with DMD present with reduced ambulation in early childhood and require the use of a wheelchair in their teens. DMD currently has no cure, with patients typically only surviving until their early twenties.
Due to the dystrophin gene being the largest protein-encoding gene in the human genome, direct replacement has thus far proved unsuccessful. As a result, a significant focus has been placed on understanding and intervening in the critical pathways responsible for advancing DMD pathology. Skeletal muscle phenotypes have been studied extensively in the disease, especially related to the diaphragm, which is known to undergo significant deterioration. However, cardiomyopathy has only recently been recognized as a significant contributor to DMD mortality. Little is known related to the DGC in the heart or the major pathways that contribute to the development of pathology. The use of mouse models of DMD, genetic knockouts of related genes, and chimeric mice have allowed for the further understanding of these important phenotypes. Analysis of the nitric oxide pathway in the heart has revealed a novel localization pattern of DGC related proteins, such as nNOS, in a manner that differs from skeletal muscle. In addition, this work has opened the door to investigation of the intercalated discs of the heart, responsible for maintaining both structural and signaling junctions, importantly related to the electrical conduction system. Analysis of connexin43 (Cx43) in DMD hearts has shown a significant protein mislocalization, characteristic of severe forms of cardiomyopathy. In addition, intervention in mdx models of DMD, which develop arrhythmias and die following -adrenergic challenge, revealed that Cx43 inhibition prevents challenge-induced arrhythmogenesis and lethality. By incorporating results from mdx/WT chimeric models of DMD, where mdx ESCs are injected into WT blastocysts, further analysis has shown that Cx43 may be one of the most significant contributors to cardiac pathology, affecting not only the electrical conduction system of the heart but also calcium handling in response to stress.
Together, these studies describe the roles of potentially critical components of DMD cardiomyopathy, and demonstrate therapeutically relevant strategies to combat human disease.

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