Meiosis in Plasmodium: How does it work?
Lead Research Organisation:
University of Nottingham
Department Name: School of Life Sciences
Abstract
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Technical Summary
The major goal of the project is to discover and understand the function of the protein substrates of a NIMA-related kinase (NEK4) and PP2C-related metallo-dependent protein phosphatase (PPM2) during Plasmodium meiosis. We showed that these enzymes are essential for sexual development of the malaria parasite in the mosquito, specifically during the earliest stages of meiosis. Plasmodium meiosis is vastly understudied and nothing is known about the protein substrates regulated by either of these enzymes. In addition, the function of any meiosis-related genes in Plasmodium are largely unexplored.
For this study we will use Plasmodium berghei as an experimentally tractable model, exploiting our established insectary, transgenic parasite resources and advanced imaging facilities. This infrastructure provides a unique research strength and capabilities to study parasite development in the sexual stages of the life cycle, which are difficult to study in human-infective malaria parasite species.
The emphasis of the project will be on Plasmodium meiosis and the protein substrates targeted by NEK4 and PPM2, as well as their function. This will be the first study to uncover the key molecular players that drive Plasmodium meiosis, while potentially discovering novel functions for their substrates. Complementary approaches will be used to pursue the three major aims of the project: protein interactomics to uncover the protein substrates of NEK4 and PPM2; phosphoproteomics to determine the global phosphorylation events they regulate; reverse genetics to systematically attempt to knockout their targets, and advanced imaging and ultrastructure analysis to determine their localisation and consequence of their absence during meiosis. This may foster further research that will significantly advance our fundamental understanding of the divergent mechanisms of Plasmodium meiosis, that may be relevant to other parasite species with huge socioeconomic impact on animal and health.
For this study we will use Plasmodium berghei as an experimentally tractable model, exploiting our established insectary, transgenic parasite resources and advanced imaging facilities. This infrastructure provides a unique research strength and capabilities to study parasite development in the sexual stages of the life cycle, which are difficult to study in human-infective malaria parasite species.
The emphasis of the project will be on Plasmodium meiosis and the protein substrates targeted by NEK4 and PPM2, as well as their function. This will be the first study to uncover the key molecular players that drive Plasmodium meiosis, while potentially discovering novel functions for their substrates. Complementary approaches will be used to pursue the three major aims of the project: protein interactomics to uncover the protein substrates of NEK4 and PPM2; phosphoproteomics to determine the global phosphorylation events they regulate; reverse genetics to systematically attempt to knockout their targets, and advanced imaging and ultrastructure analysis to determine their localisation and consequence of their absence during meiosis. This may foster further research that will significantly advance our fundamental understanding of the divergent mechanisms of Plasmodium meiosis, that may be relevant to other parasite species with huge socioeconomic impact on animal and health.
