The rapid development and spread of drug resistant Plasmodium falciparum is a serious global health problem and has contributed to increased mortality and morbidity caused by malaria. This situation has led to the adoption of artemisinin-based combination therapies (ACTs) for the management of malaria infections in many African countries including Nigeria. However, changes in antimalarial drug policies in many African countries were done without the availability of tools for large-scale monitoring of development and spread of P. falciparum resistance to the new drugs. In addition, there are concerns that parasites may soon become resistant to artemisin derivatives or partners drugs once they are introduced for management of malaria in Africa. Thus, researches leading to the definition of molecular determinants of parasites responses to artemisinin derivatives (ARTs) and partner drugs used in combination therapy are crucially needed, as they may unveil markers that are critical for efficient monitoring of drug resistant parasites as well as new chemotherapeutic targets. We hypothesized that combination of different mutations (SNPs) and/or differential expression in transporters and pfATPase6 genes of P. falciparum may be responsible for the differential in vitro or in vivo responses to artemisinin and partner drugs. Furthermore, multiple drug response determinants may be acting in different combinations resulting in differences between parasites phenotypes. This research is primarily directed at identifying and validating molecular determinants of resistance to artemisinin derivatives, lumefantrine (LUM) and amodiaquine (AQ) in fresh patients isolates of Plasmodium falciparum. Molecular determinants of parasites responses to antimalarials identified under this project will be used to develop a quick and simple high-throughput PCR-ELISA based tool/technique that detects SNPs in P. falciparum pfATPase6 and transporters genes as well as other parasites genes, for large- scale monitoring of parasites resistance to artemisinin derivatives and other antimalarials. To achieve these goals the following specific activities will be carried out over a 3 year period: 1) Evaluate the efficacy and in vitro susceptibility of P. falciparum to artemether-lumefantrine and artesunate- amodiaquine combinations in Southwest Nigeria; 2) determine parasites population diversity and assess the presence of SNPs in genes (selected transporters or pfATPase6) in fresh isolates of P. falciparum obtained from patients; 3) evaluate and compare SNPs patterns in selected P. falciparum transporters and pfATPase6 genes in patients isolates and freshly cloned parasites before and following drug (AQ, LUM and ARTs) pressure; 4)Collate SNPs patterns of transporters genes and pfATPase6 with in vitro susceptibility profile, treatment modalities in order to Identify molecular determinants of ARTs, LUM or AQ, and the development of unique resistant phenotypes; 5) use molecular determinants (SNPs) of P. falciparum response to ARTs, LUM or AQ to develop a simple high- throughput method for large-scale monitoring/surveillance of drug resistant parasites to artemisinin and partner drugs used in combination therapy for malaria in Nigeria. This research project provides a unique opportunity to use Research Infrastructures and Capacities developed in Nigeria under the FIRCA Grant no. NIH RO3TW006298, for a better understanding of the development and spread of resistance to ACTs and other antimalarial drugs. Data obtained and tools developed by this project will be made available to the Nigerian National Malaria Control Program in order to promote evidence-based antimalarial drugs policy in the country. . This research project has a direct relevance to the problem of drug resistance in Nigeria and Africa. It provides a unique opportunity to use Research Infrastructures, Capacities Developed in Nigeria under the FIRCA Grant no. NIH RO3TW006298 as well as the technologies to be developped under the current project to better understand the development and spread of parasites resistance to ACTs and other antimalarial drugs. Data obtained and tools developed by this project will be made available to the Nigerian National Malaria Control Program in order to promote evidence-based antimalarial drugs policy. ? ? ?
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