Genetic validation of essential asexual stage genes in Plasmodium falciparum

Harvard School Of Public Health, Boston MA

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Abstract

DESCRIPTION (provided by applicant): A continuous pipeline of drugs is desirable for the long-term goal of malaria eradication. The genome of the human malaria parasite Plasmodium falciparum has been sequenced providing a blueprint that can be exploited. New methods are required for the genetic validation of the essentiality of candidate proteins as targets for drug development. We will utilize a novel system for inducible protein expression to conduct a functional genetic screen to identify genes in P. falciparum that are essential for parasite growth and invasion in erythrocytes. We will conduct an exploratory screen of all parasite protein kinases expressed maximally at the schizont stage of P. falciparum development, to identify those that are required for parasite egress from and invasion into erythrocytes in P. falciparum. There are currently no approved antimalarials targeting these stages of the asexual cycle. We will conduct a molecular and cellular characterization of each candidate protein, as well as a phenotypic assessment of knockdown in expression. Such genetic validation represents a critical step in the prioritization of candidate proteins as targets for drug development. PUBLIC HEALTH RELEVANCE: Malaria eradication requires a continuous pipeline of efficacious drugs. The genome sequence of the malaria parasite has revealed numerous genes encoding proteins that can be developed as drug targets. We will establish a new approach based on a system of conditional protein expression to screen for essential genes in the malaria parasite. Such a genetic validation represents a critical step in the prioritization of the candidate proteins as targets for drug development.