Chemical Inhibition of SHIP1 To Facilitate Allogeneic Bone Marrow Transplantation

描述（由申请人提供）：我们先前证明宿主的SHIP 1表达对于同种异体BM和心脏移植物的有效排斥以及损害移植后存活的移植物抗宿主病（GvHD）是必需的。此外，我们发现，诱导SHIP1缺陷的一个短暂的时期之前，异基因骨髓移植保护移植受体急性GvHD，即使有一个完整的受体和供体之间的MHC不匹配。因此，我们提出SHIP 1的化学抑制可用于促进同种异体BM的植入和减少GvHD。本文提出的研究不仅可能增加目前实施的同种异体BMT的有效性，而且还可能通过允许供体和受体之间HLA差异程度更大的移植来增加这种疗法的效用。在这里，我们提出开发具有增加的效力和溶解度的3AC类似物以及在我们的HTS筛选中鉴定的其他SHIP 1抑制化合物的衍生物（Aim 1）。将评估3AC和其他新型SHIP 1抑制性化合物促进骨髓清除宿主移植后更快速和更稳健的植入的潜力（目的2）。此外，我们将测试这些新型SHIP 1抑制剂在同种异体BMT后消除GvHD的能力（目的3）。具体目的是：目的1：衍生新的SHIP 1抑制化合物。目的2：测试SHIP 1抑制剂促进同种异体BMT后植入的能力。目的3：测试SHIP 1抑制剂消除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.