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PhD (4th year)
Department: Microbiology & Immunology
Advisor: William Kerr, PhD
Natural killer (NK) cells express activating and inhibitory receptors, termed the Natural Killer Receptor Repertoire (NKRR), that are expressed in a variegated manner with individual receptor frequencies and densities determined not only by promoter strength, but also by the presence of MHC-I ligands. The signaling inputs from the activating and inhibitory receptors expressed by an individual NK cell determines it's ability to respond to an infected or malignant cell. Mice with germline deficiency in SHIP1 have severe NK cell dysregulation, including increased NK cell numbers, deregulated NKRR and inability to reject an MHC-mismatched bone marrow graft. It is unknown if NK cell dysfunction is due to intrinsic effects of SHIP1 in NK cells or due to the effect of SHIP1 deficiency in other immune cell types that leads to an inflammatory milieu in SHIP1-/- mice. Using a mouse model that enables NK selective ablation of SHIP1 expression, NCR1iCreSHIP1flox/flox, we have begun to assess if the defects noted previously are recapitulated in mice where only NK-lineage cells lack SHIP1 expression.
• Fuhler, G.M., Brooks, R., Toms, B., Iyer, S., Gengo, E.A., Park, M.Y., Gumbleton, M., Viernes, D.R., Chisholm, J.D., and Kerr, W.G. (2012). Therapeutic potential of SH2 domain-containing inositol-5'-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer. Mol Med 18, 65-75.
• Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, Migaud M, Israel L, Chrabieh M, Audry M, Gumbleton M, Toulon A, Bodemer C, El-Baghdadi J, Whitters M, Paradis T, Brooks J, Collins M, Wolfman NM, Al-Muhsen S, Galicchio M, Abel L, Picard C, Casanova JL. (2011 0. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science. Apr 1;332(6025):65-8.