The objective of this proposal is the validation and characterization of a chimeric human-murine liver model for the exo-erythrocytic stage of human Plasmodium infections. Additionally, liver stage parasites will be recovered from the chimeric livers, by laser capture micro-dissection, their mRNA isolated and used for microarray analysis. Among the different developmental stages of Plasmodium falciparum, the least well characterized is the hepatic or exo-erythrocytic (EE) phase. This stage encompasses the infection and multiplication of the parasite following entry into the hepatocyte and can only be studied in humans and a few non-human primates. Unfortunately, it is difficult to obtain biological material containing the EE forms of P. falciparum or P. vivax, the parasites responsible the majority of cases in humans. The studies proposed in this project will produce in vivo data on the kinetic expression of previously identified antigens and by using microarray analysis allow the identification of the parasite transcriptome during EE development. This type of global analysis has been made possible, because the entire genomic sequence of the human malaria parasite, P. falciparum has been completed. Despite the identification of the over 5,200 genes in the parasite genome, the identification of potential vaccines and drug targets will depend upon functional genomics studies combined with relational databases and informatics to determine the characteristics (identity) of each encoded protein. The analysis of the EE stage transcriptome will complement several recent genome-wide studies that have elucidated the P. falciparum proteome and transcriptome of sporozoites, merozoites, trophozoites and gametocytes. This will then produce a truly comprehensive picture of gene expression during the lifecycle of human malaria parasites. ? ?
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