Friday, March 14, 2025
3/14/2025
DESCRIPTION (provided by applicant): Over the last four years this grant has enabled us to make several novel advances including the demonstration that the SH2-containing Inositol Phosphatase (SHIP) plays a pivotal role in the biology of NK cells, Graft-Versus-Host Disease (GvHD) and rejection of allogeneic bone marrow (BM) grafts.(1-5) We find that the NK receptor repertoire (NKRR) of SHIP mice is highly disrupted with certain NK receptors (NKR) dominating the repertoire of SHIP-/- NK cells. Moreover the subset of receptors that becomes dominant in SHIP-/- NK cells can vary with allelic differences in self ligands such as MHC class I. The "receptor dominance" created by SHIP-deficiency in turn compromises cytolytic function suggesting a novel mechanism for NK dysfunction and immune deficiency. In aggregate our studies indicate SHIP regulates NKR signaling pathways that sense self ligands and that SHIP'S role is to prevent one or a few NK NKR from dominating the NKRR.(1,4,5) We hypothesize then that SHIP regulates the NKRR through signaling pathways that control survival and proliferation of NK cell subsets (indirect effects) or NKR expression (direct effects). Based on our progress to date this revised renewal application has been restructured as three aims. In Aims 1 and 2 we will define in molecular terms the signaling pathways and components of SHIP required for regulation of the murine NKRR. The revised Aim 3 has been refocused to define in molecular terms why key NK cytolytic functions are altered by SHIP-deficiency. This renewal application will be pursued in the following specific aims: Aim 1: Define self-ligand/receptor pairs, and signaling proteins recruited to them, required for regulation of the NKRR by SHIP. Aim 2: Define effector pathways altered by SHIP-deficiency that lead to NKRR disruption. Aim 3: Define the mechanisms responsible for compromised function of SHIP-/- NK cells.
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