رسالة جامعية
Allotopic RNA expression strategy to rescue an endogenous mitochondrial ATP6[1] mutation in Drosophila
| العنوان: | Allotopic RNA expression strategy to rescue an endogenous mitochondrial ATP6[1] mutation in Drosophila |
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| المؤلفون: | Towheed, Atif |
| سنة النشر: | 2015 |
| المجموعة: | University of Pittsburgh: D-Scholarship@Pitt |
| الوصف: | Mitochondria are essential organelles in the cell. One of their most critical functions is the generation of cellular energy in the form of ATP. The presence of DNA in the mitochondrial matrix makes this organelle semi-autonomous. However, it relies heavily on the nucleus and cytosol to import ~99% of its proteins and some RNA molecules for its normal functioning. Mutations in the mitochondrial DNA (mtDNA) cause several devastating disorders. Due to their complexity and our incomplete understanding of mitochondrial disease pathogenesis, these disorders are difficult to diagnose and currently no pharmacological treatment exists. Further, gene therapy for these devastating disorders is impeded due to lack of mitochondrial genome manipulation techniques. Understanding the mechanism of pathogenesis and developing mtDNA manipulation strategies are key to developing remedial therapies. In my thesis, I investigated an RNA allotopic strategy of targeting RNA into the mitochondria in vivo in flies. In my first aim, I improved an in vivo mitochondrial-targeting tool (mtTRES vector) to manipulate proteins encoded by the mitochondrial DNA. This vector integrates into the nuclear genome and results in the transcription of a chimeric RNA consisting of a mitochondrial targeting signal sequence and a small non-coding antisense RNA. Previous studies have attempted allotopic expression via both protein and RNA import with mixed results. Only a few of them, however, have been tested in vivo and none have been examined for rescue in an animal model of mitochondrial disease. Since our lab has a well characterized mtDNA mutation fly model, ATP6[1], I had a unique opportunity to investigate rescue strategies in these models. In my second aim, I improved a unique set of mtTRESPro vectors for both flies and humans to target long coding RNAs into mitochondria. Once imported these long RNAs are designed to be endogenously translated in mitochondria. By targeting a wild type copy of the mutant ATP6 gene, I explored the rescuing potential ... |
| نوع الوثيقة: | thesis |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | http://d-scholarship.pitt.edu/23999/1/Towheedatif_ETD2015.pdfTest; Towheed, Atif (2015) Allotopic RNA expression strategy to rescue an endogenous mitochondrial ATP6[1] mutation in Drosophila. Doctoral Dissertation, University of Pittsburgh. (Unpublished) |
| الإتاحة: | http://d-scholarship.pitt.edu/23999Test/ http://d-scholarship.pitt.edu/23999/1/Towheedatif_ETD2015.pdfTest |
| رقم الانضمام: | edsbas.BB8EA08 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |