Medicine, Dentistry & Health Sciences Collected Works - Theses
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ItemGenetic strategies to improve islet graft function(University of Melbourne, 2010)
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ItemAnimal models of inherited human epilepsies(University of Melbourne, 2008)
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ItemLeukocyte trafficking in the control of disease and immunity to malaria(University of Melbourne, 2010)
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ItemGenetic regulation on hematopoiesis(University of Melbourne, 2010)
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ItemPriority setting in health : contextualising program budgeting and marginal analysis (PBMA) in Indigenous health(University of Melbourne, 2010)
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ItemSexually abusive teenage males : a two-stage evaluation of three approaches to subgroup classification(University of Melbourne, 2010)
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ItemIdentification and characterisation of microRNA involved in epithelial ovarian cancer(University of Melbourne, 2010)
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ItemNovel roles for ribosomal protein mutants in regulating growth and proliferation in drosophila melanogaster(University of Melbourne, 2010)The ribosome is critical for all aspects of cell growth due to the essential role it plays in protein synthesis. Ribosomal proteins (Rps) provide vital structural support for the organisation of ribosomal RNAs (rRNAs) within the ribosome. Recently, Rp mutations have been implicated in human cancer-related diseases and overproliferation (for example, Diamond Blackfan Anemia and the 5q- syndrome). This function is counter-intuitive, as based on their ribosomal role loss of Rp function is predicted to limit growth. The work in this thesis was focused towards understanding the mechanisms whereby reductions in Rp levels could result in cellular overgrowth and malignant phenotypes. To answer the question of how reductions in Rps could lead to tissue overgrowth, the Drosophila melanogaster model system was used to carry out genetic manipulations of Rps in the whole animal. We took advantage of the observation that RpS6 behaves as a tumour suppressor in the cyclin E hypomorphic mutant (cycEJP) background, to interrogate one possible mechanism by which Rp reduction causes tissue overgrowth. The work presented in this thesis demonstrated that the suppression of cycEJP by the RpS6 mutant was not a consequence of restoring cycE protein levels in the eye imaginai tissue, nor due to affecting cycE activity. The use of UAS-RpS6 RNAi transgenics confirmed that the suppression of cycEJP was reliant on a tissue non-autonomous mechanism, as suppression of the small rough eye phenotype was only observed when RpS6 was reduced ubiquitously throughout the fly. The developmental delay associated with Rp mutations suggested that the tissue non- autonomous mechanism might be linked to a well-described endocrine mechanism for control of tissue and organ growth. This mechanism involves the release of the steroid hormone ecdysone from the prothoracic gland (PG), resulting in the coordination of animal growth with developmental timing. Indeed, previous studies had revealed that reducing PG size and therefore ecdysone synthesis results in an extended larval growth period and larger flies. We hypothesised that reducing RpS6 in the PG would limit PG growth and ecdysone release, thus delaying development and giving cycEJP eye discs extra time to grow. Experiments detailed in this thesis confirmed this hypothesis by demonstrating that reduction of RpS6 specifically in the PG was associated with reduced ecdysone activity and resulted in suppression of the cycEJP rough eye phenotype. Thus this tissue non- autonomous mechanism explains in large part the suppression of cycEJP by the RpS6 mutant. The work in this thesis also highlights the importance of considering the function of endocrine/paracrine glands in human diseases and lastly, provides for the first time a rationale to explain the overgrowth phenotypes observed in a group of Rp mutants in Drosophila, known as Minutes.
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ItemInvestigating the molecular mechanisms of apoptosis targeted therapy(University of Melbourne, 2010)