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SHIP1的表达是有效排斥异基因骨髓和心脏移植物以及危及移植后生存的移植物抗宿主病(GvHD)所必需的。此外，我们还发现，即使在供者和受者之间存在MHC完全不匹配的情况下，在异基因骨髓移植前的一段时间内诱导SHIP1缺乏症也可以保护移植受者免受急性GvHD的影响。因此，我们认为化学抑制SHIP1既可以促进同种异体骨髓的植入，又可以减少GvHD。这里提出的研究不仅可能增加目前正在进行的异基因骨髓移植的有效性，还可能通过允许供者和受者之间存在更大程度的人类白细胞抗原差异的移植来增加这种疗法的实用性。在这里，我们建议开发具有更强的效力和溶解性的3AC类似物，以及在我们的HTS筛选中确定的其他SHIP1抑制化合物的衍生物(目标1)。将评估3AC和其他新型SHIP1抑制化合物在去髓细胞移植后促进更快和更强大的植入的潜力(目标2)。此外，我们还将测试这些新型SHIP1抑制剂消除异基因骨髓移植后移植物抗宿主病的能力(目标3)。具体目标是：目标1：新的SHIP1抑制化合物的合成。目的2：检测SHIP1抑制剂促进异基因骨髓移植后植入的能力。目的3：检测SHIP1抑制剂对移植物抗宿主病的抑制作用。 与公共健康相关：我们已经确定了抑制化学物质，它可以关闭一种限制放射治疗后血细胞恢复的基因。这种基因还限制了免疫细胞的数量，这些细胞可以防止其他免疫细胞在接受别人的骨髓移植(异基因骨髓移植)后攻击患者的身体。这种抑制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产生；(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，以限制与异基因骨髓移植相关的危及生命的并发症。此外，它可能会允许无法找到完全匹配的骨髓捐赠者的人接受来自接近但不完全匹配的捐赠者的异基因骨髓移植。这将允许更多的人利用这种挽救生命的疗法来治疗血癌、某些遗传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.