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Killing of tumor cells and virus-infected cells by cytotoxic lymphocyte granule proteases

Thursday 22 January 2009

Dr. Niels Bovenschen

Project
Cytotoxic lymphocytes are the killer cells of our immune system that deal with the elimination of both tumor cells and virus-infected cells from our body. These cytotoxic lymphocytes contain granules that are released following the recognition and binding of target cells. These granules contain the pore-forming protein perforin that makes pores in the target cell membrane and a set of serine proteases (granzymes) that enter the target cell through these pores. Once inside the target cell, granzymes cleave critical substrates that in turn activate multiple routes of cell death (apoptosis). However, some tumors or viruses have evolved strategies to overcome granzyme actions and become resistant to our immune system. Granzymes also exist extracellularly in plasma in pathologic conditions like inflammation, virus infections, and autoimmunediseases. Insight into the granzyme mechanism of action is important for the development of anti-cancer, anti-viral, and anti-inflammatory therapeutic intervention.

The main research lines are:
A) Elucidation of substrates and cell death pathways of granzymes in tumor cells.
B) Identification of viral components and host cell proteins involved in the viral replication machinery as potential direct targets of granzymes.
C) Investigation of the role of extracellular granzymes during inflammation and virus infections.

Techniques
proteomics, cell biological and molecular techniques such as: SDS-PAGE, Western blotting, fluorescent 2D gel electrophoresis, recombinant protein expression, protein purification, cell culture, viral culture, FACS, PCR, and cloning

Duration
6 - 9 months

Contact
Dr. N. Bovenschen, n.bovenschen@umcutrecht.nl, tel 088 75 538 89