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Hypercontraction and Drosophila : a model system for the study of human myopathies

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dc.contributor.advisor J. Troy Littleton. en_US Montana, Enrico Sakai en_US
dc.contributor.other Massachusetts Institute of Technology. Dept. of Biology. en_US 2008-02-28T16:16:23Z 2008-02-28T16:16:23Z 2005 en_US 2005 en_US
dc.identifier.uri en_US
dc.description Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2005. en_US
dc.description Includes bibliographical references. en_US
dc.description.abstract Currently, there are no therapeutic interventions which fully alleviate the defects associated with muscular dystrophies and cardiomyopathies. Development of model systems in which to utilize high-throughput screens for novel compounds will help in drug discovery for these diseases. In addition, genetic model systems will allow us to dissect the molecular and cellular pathways activated in response to mutations that affect muscle function, increasing our understanding of the underlying physiology of normal and diseased muscles. Here we present work establishing Drosophila as a model system for human muscular dystrophies and cardiomyopathies. Characterization of hypercontraction- induced myopathy caused by mutations in Myosin Heavy Chain has led to a potential mechanism of hypercontraction through unregulated contraction cycles in mutant muscles. In addition, hypercontraction defects cause temperature-sensitive myogenic seizures due to an altered state of the muscle which is fundamentally different than normal and hypocontracted muscle. en_US
dc.description.abstract (cont.) Analysis revealed strong parallels between the genetics of flight behavior in Drosophila and familial hypertrophic cardiomyopathies in humans, suggesting that the altered state in hypercontraction muscles may reflect diseased states in mammals. Expression analysis of hypercontraction suggests a conservation of the cellular response induced in muscles which have contractile dysfunctions. This response includes the upregulation of developmentally-regulated transcripts and immune- response genes, and a downregulation of energy and metabolism genes. In addition to these parallels in transcriptional regulation in response to hypercontraction and human myopathies, a potential actin remodeling response has been uncovered. This remodeling response may be utilized in other contexts such as activity-dependent synaptic strengthening in the nervous system. Current studies on the functional consequences of differential regulation have begun. Loss-of-function mutations in the highest upregulated transcript, dARCI suggests the dARC1 protein does not mediate essential roles in synaptic transmission, short-term plasticity, learning and memory of courtship, and circadian rhythms. en_US
dc.description.abstract (cont.) It may be that dARCI underlies subtle modulation of these processes which may be inaccessible by our assays. Future studies will address its role in muscle remodeling and synaptic metaplasticity. en_US
dc.description.statementofresponsibility by Enrico Sakai Montana. en_US
dc.format.extent 233 leaves en_US
dc.language.iso eng en_US
dc.publisher Massachusetts Institute of Technology en_US
dc.rights M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. en_US
dc.rights.uri en_US
dc.subject Biology. en_US
dc.title Hypercontraction and Drosophila : a model system for the study of human myopathies en_US
dc.type Thesis en_US Ph.D. en_US
dc.contributor.department Massachusetts Institute of Technology. Dept. of Biology. en_US
dc.identifier.oclc 65196424 en_US

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