Leishmania protozoan parasites, the causative agent of leishmaniasis, a disease endemic in more than 80 countries, undergo two main developmental stages during its life cycle: the extracellular flagellated promastigote residing in the midget of the sandfly vector and the obligate intracellular amastigotes which multiply in the phagolysosome of infected macrophages within the mammalian host. The differentiation process from promastigote to amastigote allows Leishmania parasites to adapt to different environments and is essential for parasite proliferation and survival. However, the molecular events that regulate this process are not well understood. / In higher eukaryotes, cellular proliferation, differentiation and function are governed largely by protein phosphorylation, which is controlled by protein kinases and phosphatases. The research described in this thesis has investigated the role of protein tyrosine phosphatase in controlling the differentiation and proliferation of the Leishmania pathogen in different life cycle stages, by analogy to what happens in higher eukaryotes. The focus was on protein phosphatases because in general, there are fewer phosphatases than kinases in the eukaryotic cells and therefore there is less likelihood of redundancy under conditions where it is possible to genetically develop mutants in phosphatase genes. / By undertaking a predominantly genetic approach, we show the protein tyrosine phosphatase may play a role in L. donovani differentiation and is clearly required for parasite virulence as defined by survival in the mammalian host. / The results from this study suggest that Leishmania PTP1 represents a potential drug target. However it is also revealed that the overall three dimensional structure of the active site of Leishmania PTP1 is very similar to the human PTP1B arguing that it may be difficult to develop parasite specific inhibitors. Taken together this study represents the first genetic analysis of a key regulatory gene in Leishmania, which establishes the foundation for future more biochemical approaches to study protein phosphorylation in Leishmania.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.103174 |
| Date | January 2007 |
| Creators | Nascimento, Mirna G. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Microbiology and Immunology.) |
| Rights | © Mirna G. Nascimento, 2007 |
| Relation | alephsysno: 002584759, proquestno: AAINR32373, Theses scanned by UMI/ProQuest. |
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