In this second renewal we propose to pursue three new areas of investigation that are a direct consequence of advances made during the previous funding period.
In Aims 1 and 2 we will further define the role that SHIP plays in NK effector function with a focus on cytokine production and NK tolerance to host.
In Aim 3 we will capitalize on our recent identification of the first small molecules that can selectively target SHIP1 activity in vivo to determine if this novel compound can enhance cancer control by NK cells.
The specific aims are:
Aim 1 : Determine the molecular basis for defective cytokine production by SHIP-/- NK cells. During the previous funding period we made the unexpected observation that SHIP is required for effective induction of 3-IFN by major NK activating receptors like NK1.1, NCR1/NKp46 and NKG2D. In this aim we will determine how broadly SHIP- deficiency impairs production of 3-IFN and other cytokines and chemokines produced by NK cells. In addition, we will define the molecular basis of this defect.
Aim 2 : Define the role of SHIP in self tolerance by the NK cell compartment. During the previous funding period we found that the expression and representation of both murine (Ly49) and human (KIR) NK inhibitory receptors for MHC class I ligands is limited by SHIP and that SHIP preferentially plays this role in the context of high affinity MHC-I ligands for these receptors. In the case of human KIR, we provide preliminary evidence that SHIP is required to maintain NK tolerance to the host. In this aim we will determine if SHIP plays a role in NK tolerance to self and does so in the context of MHC-I ligands that vary in their affinity for NK inhibitory receptors.
Aim 3 : Test the potential of SHIP inhibitors to enhance NK cell eradication of cancer. During the previous funding period we developed the first small molecule inhibitors of SHIP enzyme activity, one of which is selective for SHIP1 and has significant activity in vivo. In addition, we demonstrated that SHIP-/- NK cells from an MHC haplotype with a high affinity MHC-I ligand demonstrate supernormal killing of allogeneic tumors that lack this ligand. SHIP is also known to limit ADCC against tumor cells by NK cells. Thus, in this aim we will determine if chemical inhibition of SHIP can improve the ability of NK cells to eradicate cancer in vivo. This will be examined in three different contexts each of which has significant potential for translation to clinical therapy.

Public Health Relevance

In this proposal we will attempt to better understand why a gene called SHIP is important for certain immune cells, called natural killer cells, to fight injection and kill tumor cells. These approaches could lead to better ways to eradicate cancer using new chemicals we have discovered that can 'turn off'SHIP.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Thomas, John
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Upstate Medical University
Schools of Medicine
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Fernandes, Sandra; Srivastava, Neetu; Sudan, Raki et al. (2018) SHIP1 Deficiency in Inflammatory Bowel Disease Is Associated With Severe Crohn's Disease and Peripheral T Cell Reduction. Front Immunol 9:1100
Somasundaram, Rajesh; Fernandes, Sandra; Deuring, Jasper J et al. (2017) Analysis of SHIP1 expression and activity in Crohn's disease patients. PLoS One 12:e0182308
Park, Mi Young; Sudan, Raki; Srivastava, Neetu et al. (2016) LRBA is Essential for Allogeneic Responses in Bone Marrow Transplantation. Sci Rep 6:36568
Srivastava, Neetu; Iyer, Sonia; Sudan, Raki et al. (2016) A small-molecule inhibitor of SHIP1 reverses age- and diet-associated obesity and metabolic syndrome. JCI Insight 1:
Russo, Christopher M; Adhikari, Arijit A; Wallach, Daniel R et al. (2015) Synthesis and initial evaluation of quinoline-based inhibitors of the SH2-containing inositol 5'-phosphatase (SHIP). Bioorg Med Chem Lett 25:5344-8
Gumbleton, Matthew; Vivier, Eric; Kerr, William G (2015) SHIP1 intrinsically regulates NK cell signaling and education, resulting in tolerance of an MHC class I-mismatched bone marrow graft in mice. J Immunol 194:2847-54
Lind, Evan F; Millar, Douglas G; Dissanayake, Dilan et al. (2015) miR-155 Upregulation in Dendritic Cells Is Sufficient To Break Tolerance In Vivo by Negatively Regulating SHIP1. J Immunol 195:4632-40
Anderson, Courtney K; Salter, Alexander I; Toussaint, Leon E et al. (2015) Role of SHIP1 in Invariant NKT Cell Development and Functions. J Immunol 195:2149-2156
Iyer, Sonia; Brooks, Robert; Gumbleton, Matthew et al. (2015) SHIP1-expressing mesenchymal stem cells regulate hematopoietic stem cell homeostasis and lineage commitment during aging. Stem Cells Dev 24:1073-81
Blanco-Menéndez, Noelia; Del Fresno, Carlos; Fernandes, Sandra et al. (2015) SHIP-1 Couples to the Dectin-1 hemITAM and Selectively Modulates Reactive Oxygen Species Production in Dendritic Cells in Response to Candida albicans. J Immunol 195:4466-4478

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