Conditional Translational Repression: a core regulatory mechanism of gene expression during development of the malaria parasite - study and applications.

Plasmodium zygote development in the mosquito midgut entails generation of an invasive, extended motile and polarised form, the ookinete, which traverses and encysts on the baso-laminar side of the midgut wall. These essential processes involve a detailed programme of cellular development that includes meiosis and occurs in a hostile, protease-rich environment. We have established that development of the zygote depends on a classic metazoan strategy of female germ-line cells, Conditional Trans lational Repression (CTR), in which, after fertilisation, a specific set of transcripts are stored and then activated in a temporal programme. We have identified a central and conserved regulator (DOZI) of CTR in the gametocyte, and are characterising a set of conserved and species-specific DOZI-associated proteins and RNA motif(s) in repressed mRNA species. I propose to establish a new laboratory working on (sexual) development of Plasmodium, and principally CTR. Specifically, we will underta ke: 1) Structure/function and environmental response/control analyses of the dynamic CTR complex during sexual development in the developing zygote/ookinete and the decaying gametocyte (and eventually of other stages). 2) Functional analyses of the repressed transcriptome. 3) Assessment of the rich potential for translation of these data to intervention strategies for malaria, other parasitic protozoa and human disease.