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Munc13-4/rab27a complex in NK cell and CTL function

Thursday 22 January 2009

Dr. Peter van der Sluijs / Drs Edo Elstak

Project
Mutations in RAB27a cause Griscelli syndrome type II (GS2). The disease is characterized by haemophagocytosis, and the inability of cytotoxic T cells and Natural Killer cells to release their lytic granule contents and kill virally infected and transdormed cells. We identified Munc13-4 as a partner of rab27a and showed that the two proteins function in the granule exocytosis pathway. Mutations in MUNC13-4 cause Familal Haemophagocytic Lymphohistiocytosis type 3 (FHL3) with symptoms that are related to, but distinct from those in GS2. In this project we propose to define the signaling pathways that lead from T cell receptor activation to rab27a and to characterize the function of the Munc13-4/rab27a complex in NK cells and CTLs.

Techniques
Molecular biology methods, lentiviral transduction, proteomics, advanced fluorescence techniques including live cell imaging, TIRF microscopy and FACS analysis.

Duration
6 or 9 months

References
Elstak ED, Te Loo M, Tesselaar K, van Kerkhof P, Loeffen J, Grivas D, Hennekam E, Boelens JJ, Hoogerbrugge PM, van der Sluijs P, van Gijn ME, van de Corput L. Pediatr Blood Cancer. 2011 Jul 13. doi: 10.1002/pbc.23253. [Epub ahead of print]

Elstak ED, Neeft M, Nehme NT, Voortman J, Cheung M, Goodarzifard M, Gerritsen HC, van Bergen En Henegouwen PM, Callebaut I, de Saint Basile G, van der Sluijs P. Blood. 2011 Jun 21. [Epub ahead of print]

Elstak E, de Jong A, van der Sluijs P. J Immunol Methods. 2011 Feb 28;365(1-2):58-66.

Neeft M, Wieffer M, de Jong AS, Negroiu G, Metz CH, van Loon A, Griffith J, Krijgsveld J, Wulffraat N, Koch H, Heck AJ, Brose N, Kleijmeer M, van der Sluijs P. Mol Biol Cell. 2005 Feb;16(2):731-41.

Contact
Dr. Peter van der Sluijs, p.vandersluijs@umcutrecht.nl, tel. 088 75 575 78

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