application abstract): Jayne Raper is an assistant professor in the Department of Medical and Molecular Parasitology at the New York University Medical Center. As one of the few parasitology departments in the country, this setting provides a uniquely focused environment for carrying out parasitology research, and is staffed by colleagues in possession a wide gamut of parasitological and methodological knowledge. Dr. Raper has worked on many aspects of African trypanosome biology since 1983. She has a particular interest in identifying trypanosome receptors and their role in the survival of the parasite; trypanosome receptors in general may constitute the Achilles heel of the parasite as they mediate the uptake of essential nutrients such as transferrin, LDL, and HDL from the host, and they are generally located in the flagellar pocket which is accessible to antibodies. Currently, these are the only known receptors in bloodstream-form trypanosomes, and only the transferrin receptor has been positively identified and cloned. This research proposal describes preliminary evidence supporting the existence of a trypanosome scavenger receptor that functions in the uptake of trypanosome lytic factor, as well as monoclonal antibodies that bind the receptor and function to block the lytic activity of TLF. Scavenger receptors in mammalian cells have multiple ligands that include native and modified proteins, and lipoproteins and lipids. Elucidation of the ligands for the trypanosome scavenger receptor may open new avenues for therapeutic intervention. The immediate goal is to purify, characterize and clone this trypanosomal scavenger receptor, and eventually to express it in a heterologous system to allow characterization of its ligands. The antibodies that recognize this receptor should provide a powerful tool for immunoaffinity purification, which is a method that the applicant has used extensively. The proposed cloning and expression studies, aided by advice from the consultants described herein, represent a career development opportunity that will provide an important battery of new methodologies to augment Dr. Raper's extensive biochemistry experience. If successful, completion of these goals will provide an important advance in the understanding of trypanosome biology, and greatly enrich Dr. Raper's ability to pursue her long-term goal of elucidating trypanosome receptors and other invariant surface proteins as potential therapeutic targets.
| Molina-Portela, Maria Pilar; Samanovic, Marie; Raper, Jayne (2008) Distinct roles of apolipoprotein components within the trypanosome lytic factor complex revealed in a novel transgenic mouse model. J Exp Med 205:1721-8 |
| Molina-Portela, Maria del Pilar; Lugli, Elena B; Recio-Pinto, Esperanza et al. (2005) Trypanosome lytic factor, a subclass of high-density lipoprotein, forms cation-selective pores in membranes. Mol Biochem Parasitol 144:218-26 |
| Lugli, Elena B; Pouliot, Michael; Portela, Maria Del Pilar Molina et al. (2004) Characterization of primate trypanosome lytic factors. Mol Biochem Parasitol 138:9-20 |
| Green, Heather P; Del Pilar Molina Portela, Maria; St Jean, Emmanuelle N et al. (2003) Evidence for a Trypanosoma brucei lipoprotein scavenger receptor. J Biol Chem 278:422-7 |
| Raper, J; Portela, M P; Lugli, E et al. (2001) Trypanosome lytic factors: novel mediators of human innate immunity. Curr Opin Microbiol 4:402-8 |
