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Biotech / Medical : XOMA. Bull or Bear? -- Ignore unavailable to you. Want to Upgrade?

To: Robert K. who wrote (8716)	2/15/1999 11:48:00 AM
From: aknahow	Respond to of 17367

If you have seen this disregard. Note the footnotes. Esp. the last one. Research Projects Dr R HEYDERMAN (1) Development of novel peptides based on leucocyte-derived antimicrobial proteins that modulate the inflammatory response to Neisseria meningitidis It is widely accepted that much of the disease process that follows meningococcal invasion results from the release of bacterial lipopolysaccharide (LPS) which triggers inflammatory cell activation and the elaboration of a wide range of inflammatory mediators. We have shown that recombinant bactericidal/ permeability increasing protein (rBPI21) blocks the polymorphonuclear (PMN) activation and phagocytosis response to N. meningitidis. This recombinant peptide is derived from a naturally occurring 55 kDa cationic protein stored in the azurophilic granules of PMNs. BPI inhibits LPS through lipid A and initiates cidal changes in bacterial membrane permeability. Others have shown that the C-terminal domain of BPI holoprotein promotes the uptake of an encapsulated E. coli by PMNs and monocytes. This project will explore the hypothesis that novel peptides based on leucocyte-derived antimicrobial proteins can be developed which block the inflammatory response to Neisseria meningitidis without prejudicing bacterial clearance. Overlapping peptides will be synthesised corresponding to the published amino acid sequences of BPI and azurocidin (a second canditate leucocyte-derived antimicrobial protein). The efficacy of these peptides will be screened using assays of bactericidal activity, PMN activation/ phagocytosis and endothelial injury. Once an active domain is identified, important chemico-structural characteristics will be assessed by varying pH and salt concentrations, and by performing serine for cysteine substitution experiments. The influence of capsule and LPS structure on the efficacy of these peptides will be assessed using both existing isogenic mutant strains of N. meningitidis and further strains generated by the student. This project will provide training in protein chemistry, cell biology, flow cytometry and molecular microbiology. References: Klein NJ, Ison CA, Peakman M, Levin M, Hammerschmidt S, Frosch M, Heyderman RS. (1996) The influence of capsulation and lipooligosaccharide structure on neutrophil adhesion molecule expression and endothelial injury by Neisseria meningitidis. J Infect Dis, 173:172-179. Weiss J, Elsbach P, Olsson I, Odeberg H. (1978) Purification and characterization of a potent bactericidal and membrane active protein from the granules of human polymorphonuclear leukocytes. J Biol Chem, 253:2664-2672. Iovine NM, Elsbach P, Weiss J. (1997) An opsonic function of the neutrophil bactericidal/permeability-increasing protein depends on both its N- and C-terminal domains. Proc Natl Acad Sci U S A, 94:10973-10978. Heyderman RS, Ison CA, Peakman M, Levin M, Klein NJ. Neutrophil response to Neisseria meningitidis: inhibition of adhesion molecule expression and phagocytosis by recombinant bactericidal/ permeability-increasing protein (rBPI21). In press. Û Research profiles/available research projects Û Back to the Pathology and Microbiology Home Page Last updated 4 November 1998