Chemical Inhibition of SHIP1 To Facilitate Allogeneic Bone Marrow Transplantation

SHIP1 的化学抑制促进同种异体骨髓移植

• 批准号: 8425109
• 负责人: William Garrow Kerr
• 金额: $ 39.09万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-10 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425109
• 关键词: Acute Graft Versus Host Disease; Aftercare; Allogeneic Bone Marrow Transplantation; Allogenic; Anemia; Autoimmune Diseases; Blood Cells; Bone Marrow Transplantation; Cells; Chemicals; Derivation procedure; Development; Effectiveness; Engraftment; Genes; Health; Heart Transplantation; Hematopoietic Neoplasms; Hemorrhage; Hereditary Disease; Immune; Infection; Inositol; Lead; Life; Mus; Patients; Phosphoric Monoester Hydrolases; Production; Radiation; Recovery; Solubility; Structure; Testing; Transplant Recipients; Transplantation; analog; graft failure; graft vs host disease; high throughput screening; improved; inhibitor/antagonist; novel; prevent; public health relevance

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.

描述（由申请人提供）：我们之前证明，宿主表达 SHIP1 对于有效排斥同种异体 BM 和心脏移植物以及损害移植后存活的移植物抗宿主病 (GvHD) 是必要的。此外，我们还发现，即使在受者和供者之间存在完全的 MHC 不匹配的情况下，在同种异体 BMT 之前短暂诱导 SHIP1 缺陷也可以保护移植受者免受急性 GvHD 的影响。然后我们提出 SHIP1 的化学抑制可用于促进同种异体 BM 的植入并减少 GvHD。这里提出的研究不仅可能提高目前所采用的同种异体 BMT 的有效性，而且还可能通过允许移植时供体和受体之间存在更大程度的 HLA 差异来提高这种疗法的效用。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 抑制化合物在清髓宿主中促进移植后更快、更稳健植入的潜力（目标 2）。此外，我们将测试这些新型 SHIP1 抑制剂在同种异体 BMT 后消除 GvHD 的能力（目标 3）。具体目标是： 目标 1：新型 SHIP1 抑制化合物的衍生。目标 2：测试 SHIP1 抑制剂促进同种异体 BMT 移植后植入的能力。目标 3：测试 SHIP1 抑制剂消除 GvHD 的能力。