This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed research is designed to contribute to the understanding of mechanisms of Leishmania survival, growth and development. The disease spectrum of leishmaniasis ranges from mild self-limiting cutaneous ulcers to a potentially fatal visceral infection, each dependant on the species of infectious parasite. Specific proteins secreted by Leishmania enable the organisms to sense, respond to, and alter their environment. Such secreted proteins are thus potential targets for the development of new compounds to prevent or treat this diseases. Currently there is no vaccine available for the prevention of transmission of these parasites. Toxic antimony compounds have been used unsuccessfully. Lipases are lipolytic enzymes that hydrolyze the ester bond of triglycerides. In other systems, lipase activity is involved in the reorganization of membrane structure, cell signaling or nutrient acquisition. These observations suggest that lipase activity is essential for Leishmania although presently the biological significance of this enzyme has not been proven experimentally. The working hypothesis, that lipase is essential to Leishmania, will be tested. The following approaches to determine the role of this enzyme in the parasite life cycle are planned: 1) The full-length copy of the lipase gene will be identified and characterized; the expression of lipase will be examined though out the parasite developmental life cycle and the phylogenic conservation of lipase among kinetoplastid protozoa will be determined. 2) Null-mutants deficient in lipase activity will be generated and tested for viability. 3) The lipase gene will be expressed as a recombinant protein and assayed for substrate preference. In addition, various classes of organophosphate inhibitors of lipase will be tested to determine the sensitivity of the leishmanial lipase to these compounds.
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