Characterization of glycoproteins from the flagellar pocket and endocytic pathway and the role of actin in polarized traffic in African trypanosomes. (360G-Wellcome-061205_Z_00_B)

£298,842

African trypanosomes are protozoan parasites responsible for sleeping sickness in man and Nagana in cattle and represent a significant problem in sub-Saharan Africa. A long list of discoveries has also made these cells fashionable vehicles for biological research. Although these parasites are obligatorily dependent on the uptake of factors from their mammalian hosts, our understanding of the molecular machinery involved is very limited. Endocytosis in trypanosomes occurs at rates far higher than in any other cell but is entirely limited to a tiny area of the cell surface termed the flagellar pocket (FP). The basis of this sequestration and the high rate of endocytosis of receptors is unknown. Potentially, the endocytic machinery of the FP is an area of vulnerability for the trypanosome and represents an access point for therapeutic intervention. The aim of this proposal is to exploit new results reported by the applicant to advance this possibility. These new data suggests that N-glycans containing linear poly-N-acetyllactosamine (pNAL) might act as sorting signals in endocytosis in these cells and several objectives are proposed: First the presence of pNAL has allowed the specific purification of proteins from the FP/endocytic pathway using tomato lectin. This has solved a major technical problem in the field. A range of proteins from the FP/endocytic pathway have now been purified. Antibodies have been raised against these proteins (native and deglycosylated) and expression cloning of the genes is feasible. Second, it proposes to characterise the protein(s) in the FP interacting with the pNAL sorting signal. Third, attempts will be made to exploit insect or procyclic forms of the parasite, where receptor mediated endocytosis does not occur, to re-constitute elements of the bloodstream stage endocytic pathway. Overall, this proposal has the potential to shed new light on this exigent area of research.

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Grant Details

Amount Awarded 298842
Applicant Surname Nolan
Approval Committee Immunology and Infectious Disease Funding Committee
Award Date 2006-06-29T00:00:00+00:00
Financial Year 2005/06
Grant Programme: Title Senior Research Fellowship Basic
Internal ID 061205/Z/00/B
Lead Applicant Dr Derek Nolan
Partnership Value 298842
Planned Dates: End Date 2009-12-31T00:00:00+00:00
Planned Dates: Start Date 2006-12-01T00:00:00+00:00
Recipient Org: Country Ireland
Region Ireland
Sponsor(s) Dr Paul Voorheis