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: 8588988
• 负责人: William Garrow Kerr
• 金额: $ 40万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588988
• 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）：我们先前证明，宿主的Ship1表达对于有效排斥同种异体BM和心脏移植以及损害移植后生存后的移植物抗宿主病（GVHD）是必要的。此外，我们还表明，即使接受者和供体之间的MHC不匹配，同种异体BMT之前的短时间内诱导船舶1-缺陷会保护移植受者免受急性GVHD的影响。然后，我们建议使用化学抑制Ship1既可以促进植入同种异体BM并减少GVHD。这里提出的研究不仅可能会增加同种异体BMT的有效性，而且还可以通过允许供体和受体之间HLA差异更大的移植物来增加该疗法的实用性。在这里，我们建议在我们的HTS筛选中开发具有效力和溶解度增加的3AC类似物以及其他Ship1抑制化合物的衍生物（AIM 1）。将评估3AC和其他新型Ship1抑制性化合物的潜力，以评估骨髓释放后移植后更快，更健壮的植入植物（AIM 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（AIM 3）。具体目的是：目标1：新型Ship1抑制性化合物的推导。 AIM 2：测试同种异体BMT后Ship1抑制剂促进植入的能力。目标3：测试Ship1抑制剂消除GVHD的能力。