Role of SHIP in NK Cell Biology

描述（由申请人提供）：在过去的四年中，该基金使我们能够取得几项新的进展，包括证明含SH 2的肌醇磷酸酶（SHIP）在NK细胞生物学、移植物抗宿主病（GvHD）和同种异体骨髓（BM）移植物排斥反应中起着关键作用。(1-5)我们发现，NK受体库（NKRR）的SHIP小鼠是高度破坏某些NK受体（NKR）占主导地位的SHIP-/- NK细胞的库。此外，在SHIP-/- NK细胞中占主导地位的受体亚群可以随着自身配体如MHC I类的等位基因差异而变化。由SHIP缺陷产生的“受体优势”反过来损害细胞溶解功能，这表明NK功能障碍和免疫缺陷的新机制。总的来说，我们的研究表明，SHIP调节NKR信号通路，感觉自我配体和SHIP的作用是防止一个或几个NK NKR主导NKRR。（1，4，5）我们假设SHIP通过控制NK细胞亚群的存活和增殖（间接效应）或NKR表达（直接效应）的信号通路调节NKRR。根据我们迄今为止的进展，修订后的续期申请已被重组为三个目标。在目标1和2中，我们将从分子水平定义调节鼠NKRR所需的信号通路和SHIP组分。修订后的目标3已被重新集中在分子方面定义为什么关键的NK细胞溶解功能被SHIP缺陷改变。该更新申请将在以下具体目标中进行：目标1：定义SHIP调节NKRR所需的自身配体/受体对以及向其募集的信号蛋白。目的2：定义由SHIP缺陷改变的效应子途径，导致NKRR破坏。目的3：明确SHIP-/- NK细胞功能受损的机制。

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.