The purpose of this proposal is to enable the principal investigator to develop research skills in fundamental science, in the specific area of infectious disease and molecular parasitology, to facilitate his development into an independent investigator capable of initiating and sustaining a research program. The proposal consists of two phases. The first phase is a research training phase, including didactic elements and laboratory research, which progresses to a more research-intensive and independent second phase. The principal investigator has identified the field of parasitology and tropical medicine as one in which he wishes to pursue a research career. The specific area of the research proposal, in both phases, concerns Trypanosoma cruzi, the causative agent of Chagas' disease, a chronic illness affecting over 20 million people in Mexico, Central and South America. This obligate intracellular parasite has a complex life cycle, with multiple developmental stages in the insect vector and the mammalian host. The immune system of the host mounts a strong response to the organisms but sterile immunity is rarely if ever achieved, as the parasite lies protected in the cytoplasm of host cells during its replicative phase. Gene cloning has recently revealed that several surface glycoproteins from the infective stages of Trypanosoma cruzi, which were identified by disparate means and were thought to be functionally distinct, are actually members of a large family. The variation among these sequences (as yet unpublished) is large: indeed, the relationship between some sequences that are now presumed to be members of the family night not have been noted if they did not all contain two copies of an amino acid motif that was previously identified as being unique to a group of bacterial neuraminidases (it is not shared by viral neuraminidases). More extensive searches of protein databases suggest that this motif is very rare and very significant, and that it may also be found in several proteins whose functions involve sugar recognition. Individual cells appear to simultaneously express multiple members of this gene family, which may be the key to the virulence and pathogenicity of Trypanosoma cruzi. The purposes of the proposed research are to define the enzymatic and glycan-binding activities of individual members of the gp85 family, to study the regulation of gp85 gene expression (both in individual infective cells, in clones, and during the life cycle), and to determine whether these activities are important in host cell penetration by Trypanosoma cruzi.
| Medina-Acosta, E; Paul, S; Tomlinson, S et al. (1994) Combined occurrence of trypanosomal sialidase/trans-sialidase activities and leishmanial metalloproteinase gene homologues in Endotrypanum sp. Mol Biochem Parasitol 64:273-82 |
