Trypanosoma brucei is a group of pathogenic protozoans causing a spectrum of infectious human and related animal diseases that can be fatal and economically devastating. The long term goal of the application is to determine how translational control might regulate gene expression patterns in T. brucei that underlie its growth, differentiation and pathogenesis. It attempts to establish a rational framework in understanding how different genes, which are not controlled by transcription in this organisms, might coordinate their expression by translational means during the parasite's complex life cycle between its human and insect hosts. To examine this problem, the study will focus on elucidating the biological roles and translational functions of 4 different homologues of elF4E in this organism. They display unique structural features from those of their human hosts. In many organisms elF4Es play central role in the recruitment of mRNAs in translation and act as key growth and differentiation regulator by virtue of their rate limiting and coordinating function in translation initiation and thus, proven to be good target for anti-tumor drugs in humans. Their roles in Trypanosome biology is unclear, but elucidation of their function might yield promising avenues for drug design. To accomplish these aims the homologues would be systematically down-regulated by RNAi for their expression and examine the consequences of their loss in the growth, cell cycle and differentiation of the parasite. Their protein associations and mRNA targets will also be examined by affinity purification-Mass spectrometry, and mRNA co-immunoprecipitation, respectively, to determine their mechanistic functions and their downstream gene targets for regulation. Therefore these studies should provide crucial insights into how elF4E-dependent translation impacts the sun/ival of these important parasites. This study should be relevant in unveiling gene expression control pathways, perhaps unique to the parasite, that underlie cellular processes required in adapting to diverse and harsh host environments. The potential of 4E homologues to play central roles in this process can pave the way for possible avenues for drug targeting.
