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Title: Screening for drugs to treat myotonic dystrophy
Author: Li, Xin
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2014
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Myotonic Dystrophy (DM) is the most common form of muscular dystrophy in adults with an occurrence of about 1 in 8000 people. DM type 1 (DM1) is caused an expanded CTG triplet repeat within the 3' -untranslated region (3' -UTR) of the Myotonic Dystrophy protein kinase (DMPK) gene, while type 2 (DM2) is caused by an expanded CCTG repeat in intron I of the Zinc Finger 9 gene (ZNG9) gene. In DM, the mutant DMPK transcripts are trapped within nucleus and fOlm ribonuclear foci which interact with alternative splicing factors including MBNL and CUG-BP proteins. The abnormal levels of splicing factors lead to splicing defects contributing to the major symptoms of DM. At present, there is no treatment for DM. This study developed a series of screening and validation assays targeting different stages of DM pathophysiology. The subject of this thesis was to identify compounds and small molecules which are able to rescue molecular features of DM as a stat1ing point of therapeutic dmg development for DM. In this study, I have developed a high-throughput screen assay using an in situ hybridization protocol for compounds intenupting nuclear foci in DM patient cell lines. Enzo® Kinase, Phosphatase Inhibitor and NCGC Phatmaceutical Libraries were screened, and four compounds, Hypericin, Ro 31-8220, Gemcitabine and Chromomycin A3, which reduce or remove nuclear foci in DM cells, have been identified. Cyototoxic activities of hit compounds and their effects on molecular features of DM were examined with a series of validation assays. This study demonstrates that Ro 31-8220 alters the ratio of expansion allele of DMPK in the nucleus; Ro 31-8220 and Chromomycin A3 affect alternative splicing of SERCAl in some DMl cell lines, and eliminate or reduce nuclear MBNLl protein foci. The hit compounds identified can be a stat1ing point for dmg development for DM therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available