: The objective of this proposal is to study telomere structure and function in Trypanosoma brucei and to explore the potential of T. brucei as a model system, to contribute to the understanding of telomere structure, synthesis and regulation in mammalian cells.
The specific aims are (1) to identify and characterize proteins that interact with telomeric repeats in T. brucei and (2) to characterize the telomerase complex of T. brucei. African trypanosomiasis has two major manifestations: the human disease known as Sleeping Sickness and the animal disease Nagana (meaning loss of spirits in the Zulu language). Trypanosomiasis is endemic in equatorial Africa, where it is transmitted, among humans and animals, by Glossina, the Tsetse. The native African fauna are almost universally infected, providing a vast reservoir of potential human pathogens. Focal human epidemics are a serious reality and an increasing threat. If untreated, trypanosomiasis is rapidly fatal, and probably kills around 100,000 people annually. The available treatments are unsatisfactory and often ineffective. One of the major reasons for the persistence of African trypanosomes is their unique and efficient mechanism to evade the mammalian immune response. In a process known as Antigenic Variation, the majority of the trypanosome population is destroyed by the immune responses to a variant surface glycoprotein (VSG) coat, but individual trypanosomes switch their VSG, using a repertoire of hundreds of VSG genes, evade destruction, and seed successive waves of parasitemia. To be expressed, a VSG gene has to be located at a telomeric 'expression site'. Although antigenic variation has drawn attention to trypanosome telomeres, there has been almost no research targeted specifically to understanding trypanosome telomere structure and maintenance. Mammalian telomeres have attracted much attention, because of their central role in cell senescence and cancer. As most somatic mammalian cells replicate, their telomeres shorten, placing a limit on the number of times a cell can divide. Overcoming this restriction, by reactivating telomerase, is a necessary step among the many genetic changes that lead to cancer. Because of this, drugs that target telomerase are being sought for the treatment of cancer. Such drugs could also be valuable in the treatment of trypanosomiasis. There are significant similarities between the telomeres of trypanosomes and humans, so trypanosomes would be a useful model in which to study events that are relevant to human aging and cancer.
