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Download Unravelling the molecular pathways of Plasmodium falciparum programmed cell death: identification of novel therapeutic targets.
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NUS Graduate School for Integrative Sciences and Engineering Research Project Write-up Title of Project : Unravelling the Molecular Pathways of Plasmodium falciparum Programmed Cell Death: Identification of Novel Therapeutic Targets Name of Supervisor : Dr. Kevin SW Tan Contact Details: [email protected] Short Description Programmed cell death (PCD) is now accepted as a well-established phenomenon among the Protozoa. Despite recent reports strongly suggesting that PCD occurs in the malaria protozoan parasite Plasmodium falciparum, there is limited information on pathways and molecules that induce plasmodium cell death. The objectives of this study are to perform morphological characterization of P. falciparum PCD using transgenic parasites, to delineate the PCD pathway(s) (caspase-dependent and/or caspase-independent), and to identify and characterize plasmodial genes and proteins implicated in malaria PCD. We hypothesize that P. falciparum exhibits multiple cell death activation pathways of which unique molecular regulators are potential candidates for intervention strategies. Preliminary studies in our laboratory have suggested that the antimalarial chloroquine and mammalian apoptosis inducer staurosporine induce apoptosis-like features in P. falciparum erythrocytic stages, including early loss of mitochondrial outer membrane potential and caspase-like activity. Therefore, we proposed to initiate our study by PCD induction using a variety of drugs and assaying for typical apoptotic features including externalization of phospatidylserine, loss of mitochondria transmembrane potential, caspase-like activity, DNA fragmentation, and cell membrane changes. The use of specific inhibitors and substrates to caspase or non-caspase proteases with these assays will aid in understanding the nature of PCD-associated molecules and in delineating parasite PCD pathways. We will also characterize the function of malaria metacaspase (PfMCA1) gene in relation to its apoptotic function via functional heterologous complementation of YCA1 (ScMCA1) metacaspase KO Saccharomyces cerevisiae mutants. Additionally, novel mediators of malaria PCD will be identified via microarray analysis and the use of biotinylated caspase/ cysteine protease inhibitors. Establishment of a functional link between these molecules and malaria PCD will allow them to serve as potential chemotherapeutic targets for pharmacological activators that selectively induce/upregulate the cell death machinery in the parasite, hence limiting growth and ameliorating the disease they cause.