The African trypanosomes are responsible for causing several important diseases of humans and animals in Africa. This proposal describes a series of experiments which are aimed at understanding the unusual way in which these protozoan parasites express their genes, particularly those involved in their ability to confer disease. Our work encompasses the evolution of the genes themselves, their transcription and translation, and the processing of their polypeptide products. These areas have been intensely studied in recent years and the findings have identified several novel pathways operating in these primitive organisms. Those of major interest to us are: the phenomenon of antigenic variation, by which the parasites evade the immune system of their hosts through altering the glycoprotein composition of their surface coat in an extensive but orderly way; the process by which genes are transcribed to give chimeric mRNAs whose 5'-end is common to many such messages; and, the manner in which these parasites specifically regulate their gene expression to adapt to the different physiological environments presented by their insect and mammalion """"""""hosts"""""""". Our approach to understanding these phenomena is to determine their component steps through their dissection and reconstitution in vitro. The particular processes under detailed investigation are: 1. the evolution of the antigenic repertoire; 2. the COOH-terminal processing involving the replacement of an oligopeptide tail with a glycolipid anchor; 3. the manner by which chimeric mRNAs are generated through the discontinuous transcription of two unlinked loci; 4. the function of the common oligonucleotide segment found at the 5';-end of mnany if not all mRNAs, and; 5. the mechanism by which stage-specific genes are identified and regulated in the genome. Because of their novelty, these pathways possess not only inherent interest, but also a potential application in the design of new strategies for targeted chemotherapeutic attack
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