We previously demonstrated that SHIP1 expression by the host is necessary for efficient rejection of allogeneic BM and cardiac grafts and the Graft-versus-Host Disease (GvHD) that compromises post-transplant survival. In addition, we showed that induction of SHIP1- deficiency for a brief period prior to allogeneic BMT protects a transplant recipient from acute GvHD even when there is a complete MHC mismatch between the recipient and the donor. We propose then that chemical inhibition of SHIP1 could be used to both facilitate engraftment of allogeneic BM and reduce GvHD. The studies proposed here could potentially increase not only the effectiveness of allogeneic BMT as it is currently practiced, but might also increase the utility of this therapy by allowing transplants with a greater degree of HLA disparity between donor and recipient. Here we propose to develop 3AC analogs with increased potency and solubility as well as derivatives of other SHIP1 inhibitory compounds indentified in our HTS screen (Aim 1). The potential for 3AC and other novel SHIP1 inhibitory compounds to promote more rapid and robust engraftment post-transplant in myeloablated hosts will be assessed (Aim 2). In addition, we will test the ability of these novel SHIP1 inhibitors to abrogate GvHD following allogeneic BMT (Aim 3).
The specific aims are:
Aim 1 : Derivation of novel SHIP1 inhibitory compounds.
Aim 2 : Test the ability of SHIP1 inhibitors to facilitate engraftment following allogeneic BMT.
Aim 3 : Test the ability of SHIP1 inhibitors to abrogate GvHD.
We have identified inhibitory chemicals that can turn off a gene that limits recovery of blood cells after radiation treatment. This gene also limits the number of immune cells that prevent other immune cells from attacking a patient's body after they receive a bone marrow transplant from somebody else (allogeneic bone marrow transplantation). This inhibitory chemical does not appear to adversely impact the health of normal mice. Here we will test whether these chemicals can: (1) help mice recover normal blood cell production after allogeneic bone marrow transplantation and (2) protect mice from a lethal immune attack after bone marrow transplant. These studies could lead to the development of a novel treatment to limit life-threatening complications associated with allogeneic bone marrow transplant. In addition, it might allow people who are unable to find a perfectly "matched" BM donor to undergo allogeneic bone marrow transplant from a close, but not perfectly matched, donor. This would allow more people to take advantage of this life-saving therapy in blood cancers, certain genetic diseases and severe autoimmune disease.
|Iyer, Sonia; Viernes, Dennis R; Chisholm, John D et al. (2014) SHIP1 regulates MSC numbers and their osteolineage commitment by limiting induction of the PI3K/Akt/?-catenin/Id2 axis. Stem Cells Dev 23:2336-51|
|Maxwell, M J; Srivastava, N; Park, M-Y et al. (2014) SHIP-1 deficiency in the myeloid compartment is insufficient to induce myeloid expansion or chronic inflammation. Genes Immun 15:233-40|
|Park, M Y; Srivastava, N; Sudan, R et al. (2014) Impaired T-cell survival promotes mucosal inflammatory disease in SHIP1-deficient mice. Mucosal Immunol 7:1429-39|
|Fernandes, Sandra; Iyer, Sonia; Kerr, William G (2013) Role of SHIP1 in cancer and mucosal inflammation. Ann N Y Acad Sci 1280:6-10|
|Iyer, Sonia; Margulies, Bryan S; Kerr, William G (2013) Role of SHIP1 in bone biology. Ann N Y Acad Sci 1280:11-4|
|Hadidi, S; Antignano, F; Hughes, M R et al. (2012) Myeloid cell-specific expression of Ship1 regulates IL-12 production and immunity to helminth infection. Mucosal Immunol 5:535-43|
|Fuhler, Gwenny M; Brooks, Robert; Toms, Bonnie et al. (2012) Therapeutic potential of SH2 domain-containing inositol-5'-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer. Mol Med 18:65-75|
|Hazen, Amy L; Diks, Sander H; Wahle, Joseph A et al. (2011) Major remodelling of the murine stem cell kinome following differentiation in the hematopoietic compartment. J Proteome Res 10:3542-50|