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。 公共卫生相关性：我们已经确定了抑制性化学物质，可以关闭一个基因，限制放射治疗后血细胞的恢复。这种基因也限制了免疫细胞的数量，防止其他免疫细胞在接受其他人的骨髓移植（同种异体骨髓移植）后攻击患者的身体。这种抑制性化学物质似乎不会对正常小鼠的健康产生不利影响。在这里，我们将测试这些化学物质是否可以：（1）帮助小鼠在异基因骨髓移植后恢复正常的血细胞生成，（2）保护小鼠在骨髓移植后免受致命的免疫攻击。这些研究可能导致开发一种新的治疗方法，以限制与同种异体骨髓移植相关的危及生命的并发症。此外，它可能允许那些无法找到完全“匹配”的BM供体的人接受来自接近但不完全匹配的供体的同种异体骨髓移植。这将使更多的人能够利用这种挽救生命的疗法来治疗血癌、某些遗传性疾病和严重的自身免疫性疾病。

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. PUBLIC HEALTH RELEVANCE: 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.