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Molecular mechanisms of plasmodium falciparum sexual development: a n integrated approach

Objective

* To elucidate the molecular mechanisms regulating sexual differentiation and gametogenesis in the human malaria parasite Plasmodium falciparum.
* To identify potential anti-malarial compounds based on chemical inhibitors of protein kinases involved in the regulation of parasite growth and/or development.
Expected Outcome

The studies on the molecular mechanisms of Plasmodium differentiation are likely to bring a considerable increase in our understanding of the basic biology of the parasite. It is reasonable to expect that the results of the proposed work will include the identification of components of regulatory networks that are vital to the parasite, and hence will be of significance in the context of novel drug design.
Our attempt to identify parasite-specific CDK inhibitors is an example of the exploitation of results from fundamental studies towards drug development. Although the outcome of such screening approaches is difficult to predict, prospects are promising in the present case, as some of the compounds that will be tested have already been shown to have different IC50s on CDKs from different organisms.
The regulation of P. falciparum sexual development requires the tight coordination of several cellular and biochemical processes, such as the control of cell cycle progression and of initiation of DNA synthesis, differential morphogenesis, and stage-specific gene transcription. These processes are likely to be coordinated via signal transduction pathways that are activated by the (as yet unknown) stimuli triggering differentiation. The strategy we will follow to approach this problem will consist of the integration of different lines of investigations:

* Comparative biochemical and molecular biology studies using wild-type parasites and mutant parasite lines which have lost the ability to undergo sexual development.

* Identification and characterisation of signal transduction pathways potentially involved in the sexual development of the parasite.

* Study of the interface between the control of initiation of DNA synthesis and upstream signal transduction pathways in the context of gametocytogenesis (cell cycle arrest, inhibition of DNA synthesis) and gametogenesis (sudden release from cell cycle arrest, active DNA synthesis).

* Study of gametocyte-specific transcription and its interface with upstream signal transduction pathways, using the promoter of the early gametocytogenesis marker antigen Pfg25/27 as a model.

* Screening of protein kinase inhibitors as potential antimalarials. Available data on signal transduction and cell cycle control in P. falciparum indicate that many genes involved in these processes are conserved in the parasite; these include cyclin-dependant kinases (CDKs), several homologues of which have been identified in P. falciparum. The possibility that these enzymes may represent targets for new chemotherapeutic agents will be investigated. The IC50 of several hundred derivatives of CDK chemical inhibitors will be determined on parasite cultures, human cells lines, and in vitro kinase assays with purified CDKs from both sources. The purpose of these experiment is to identify compounds inhibiting preferentially the parasite's (versus the host's) CDKs, as the first step towards the development of novel antimalarials.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Address
Boulevard De L'h(pital 91
75643 Paris
France

Participants (5)

Istituto Superiore di Sanità
Italy
Address
Viale Regina Elena 299
00161 Roma
UNIVERSITY OF EDINBURGH
United Kingdom
Address
King's Building, Darwing Building, Mayfield Road
EH9 3Jr Edinburgh
UNIVERSITY OF NAIROBI
Kenya
Address
Riverside Drive, Chiromo Campus
Nairobi
University of Zimbabwe
Zimbabwe
Address

20 Harare
University of the Witwatersrand
South Africa
Address
7,York Road 7
2193 Parktown Johannesburg