Investigating the Molecular Mechanisms of Splicing-Perturbing Small Molecules with Massively Parallel Sequencing in a Myotonic Dystrophy 1 Model
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Date
2014-06
Authors
Tanner, Matthew
Journal Title
Journal ISSN
Volume Title
Publisher
University of Oregon
Abstract
Myotonic dystrophy is the most common form of adult-onset muscular dystrophy and appears in two forms: myotonic dystrophy 1 (OM 1) and 2 (DM2). Both
diseases arc characterized by progressive muscle degeneration, myotonia, iridescent, cataracts, and in severe cases neurodcgcncration and cardiac dysfunction. Both forms of myotonic dystrophy are caused by an expansion of repeat DNA in distinct loci in the genome. In DM1, a CTG repeat is expanded from less than 50 repeats in normal individuals to up to several thousand repeats in DM1 patients. The molecular basis of this disease relics on the transcription of these repeats from DNA into RNA. Small molecules that can specifically target the repeats at the DNA level and inhibit their
transcription - and thus alleviate the disease symptoms - represent a prime target for the
development of therapeutics. This study investigates the capacity of two small molecules, pentamidine and actinomycin D, to reverse the molecular symptoms of DM1 through transcriptional inhibition and provides insight into their DNA target specificity and potential mechanisms of action.
Description
52 pages. A thesis presented to the Department of Chemistry and Biochemistry, and the Clark Honors College of the University of Oregon in partial fulfillment of the requirements for degree of Bachelor of Science, Spring 2014.
Keywords
Biochemistry, Biology, Chemistry, Genetic disease, Myotonic dystrophy, Splicing, DNA sequencing, Small molecules, RNA