Chemical Inhibition of SHIP1 To Facilitate Allogeneic Bone Marrow Transplantation

描述（由申请人提供）：我们之前证明，宿主表达SHIP1对于同种异体骨髓和心脏移植物以及移植物抗宿主病（GvHD）的有效排斥是必要的，移植物抗宿主病会损害移植后的生存。此外，我们发现，即使受体和供体之间的MHC完全不匹配，在同种异体骨髓移植前短暂诱导SHIP1-缺陷也能保护移植受体免受急性GvHD的影响。因此，我们提出化学抑制SHIP1可用于促进同种异体骨髓移植和降低GvHD。本文提出的研究不仅可以潜在地提高同种异体骨髓移植的有效性，而且可以通过允许供体和受体之间HLA差异更大程度的移植来增加这种治疗的效用。在这里，我们建议开发具有更高效力和溶解度的3AC类似物，以及我们在HTS筛选中发现的其他SHIP1抑制化合物的衍生物（目的1）。将评估3AC和其他新型SHIP1抑制化合物在骨髓清除宿主移植后促进更快和更强的植入的潜力（目的2）。此外，我们将测试这些新型SHIP1抑制剂在异基因BMT后消除GvHD的能力（目的3）。具体目的是：目的1：衍生新的SHIP1抑制化合物。目的2：测试SHIP1抑制剂促进同种异体骨髓移植后移植的能力。目的3：测试SHIP1抑制剂抑制GvHD的能力。

DESCRIPTION (provided by applicant): 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.