The most abundant lysosomal cysteine proteinase is cathepsin B, and we are interested in its role in tumor invasion. Both the cDNA and genomic clones of human cathepsin B have been generated in our laboratory. We now plan to up- and down-regulate cathepsin B proteinase activity by antisense and over-expression vectors in murine and human tumor cells, in order to demonstrate a direct correlation between proteinases and cancer metastasis. Cystatins are inhibitors of cysteine proteinases. The coordinate regulation of cathepsin B and these proteinase inhibitors at the nucleic acid and protein levels is another related topic. In the future, the role of proteinases in other pathological conditions, such as inflammation, will also be investigated.
Our work on lysosomal proteinases has led us to study Leishmania mexicana, a parasitic protozoan that lives in the lysosome of the mammalian macrophage. During cell differentiation there is a change from motile to sessile forms of this protozoan, and we have concentrated on the leishmania cytoskeleton. Based on sequence comparison. the leishmania tubulin is similar to that of plants. Based on this information. we have found herbicides that can selectively inhibit leishmania growth, but have no effect on mammalian cells. Thus, antitubulin compounds may be potential anti-leishmania agents.
Our experience in leishmania has led to a project on oyster parasitic protozoans. The oyster industry in New Jersey has been almost totally destroyed by a parasitic protozoan, Haplosporidium nelsoni. We are planning to develop a DNA probe specific for the parasite.