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Molecular control of surface expression of the transferrin receptor in the bloodstream form of trypanosoma brucei

Objective



Research objectives and content The African trypanosome Trypanosoma brucei can multiply for years in the bloodstream of mammalian hosts. The growth of bloodstream form (BF) trypanosomes is dependent on the receptor-mediated uptake of host macromolecules such as transferrin and low-density lipoprotein (LDL). This takes place only in a specialized surface structure known as the flagellar pocket. The trypanosome transferrin receptor (Tf-R) is attached to the membrane by a glycosyl phosphatidylinositol (GPI) carboxy-terminal tail and is expressed exclusively in the membrane and lumen of the flagellar pocket. I propose to investigate the molecular mechanism involved in the polarized surface expression of trypanosome Tf-R. First, I plan to identify the domain of trypanosome Tf-R which is necessary for pocket retention. The strategy includes the generation of chimeric Tf-R, containing domains of the variable surface glycoprotein (VSG), a GPI-anchored protein expressed on the entire surface of trypanosomes. In addition, I will investigate whether the domain mediating pocket retention is involved in internalization and of trypanosome Tf-R after binding host transferrin. The second part of the project would then be the isolation of molecules that recognize these domain and thereby interact with Tf-R in BF trypanosomes. Training content (objective, benefit and expected impact) I will be trained in the molecular biology of protozoan parasites and to cultivate trypanosomes in vitro and in animals. Furthermore, I will learn to perfom gene targeting experiments in T. brucei which are routinely done in the host lab. I will learn methods for isolating proteins that interact with a given target protein. In the future I want to use the experimental system to investigate the molecular mechanism involved in the expression, targeting and internalization of other surface molecules in trypanosomes. Links with industry / industrial relevance (22)

Funding Scheme

RGI - Research grants (individual fellowships)

Coordinator

Nederlands Kanker Instituut
Address
121,Plesmanlaan
1066 CX Amsterdam
Netherlands