A Novel Bioenergetic Strategy to Treat GVHD

治疗 GVHD 的新型生物能策略

• 批准号: 8000738
• 负责人: JAMES L. M. FERRARA
• 金额: $ 23.67万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000738
• 关键词: Activated Lymphocyte; Allogeneic Bone Marrow Transplantation; Allogenic; Animal Model; Benzodiazepines; Bioenergetics; Bone Marrow Transplantation; Clinical; Complication; Development; Disease; Glycolysis; Hematopoietic Stem Cell Transplantation; Histocompatibility Antigens; Histologic; Human; Immunologics; Inflammatory; Instruction; Leukocytes; Lymphocyte; Malignant - descriptor; Malignant Neoplasms; Metabolic; Mitochondria; Modality; Molecular Mechanisms of Action; Myelogenous; Patients; Peripheral Blood Mononuclear Cell; Population; Proton-Translocating ATPases; Reactive Oxygen Species; Sampling; Stress; Therapeutic; analog; cytokine; cytotoxic; graft versus host disease induction; graft vs host disease; improved; mouse model; novel; reconstitution

PROJECT SUMMARY (See instructions): Graft versus host disease (GVHD) remains a major and intractable complication of allogeneic bone marrow transplantation (BMT). Two major effector mechanisms of GVHD are inflammatory cytokines and activated lymphocytes. In this new project, we explore a novel bioenergetic strategy to eliminate lymphocyte effectors in GHVD. Preliminary studies show that during GVHD lymphocytes that are chronically activated by histocompatibility antigens of the host have abnormal bioenergetic profiles. GVHD effector lymphocytes have low levels of glycolysis compared to acutely activated lymphocytes and show signs of mitochondrial stress, including elevated levels of reactive oxygen species (ROS). Effector lymphocytes can be selectively induced to apoptose with a cytotoxic benzodiazepine, Bz-423, that inhibits a mitochondrial ATPase. Administration of Bz-423 beginning seven days after induction of GVHD in two separate mouse models reverses GVHD by all clinical and histologic parameters and significantly improves long term survival. This project will investigate the molecular mechanisms of action of Bz-423 and explore its effects on the bioenergetic profiles of critical cellular subpopulations during hematologic and immunologic reconstitution after BMT in these animal models. This project will also define the bioenergetic profiles of leukocyte subpopulations in clinical samples from human allogeneic BMT recipients. Our Specific Aims are: 1. To analyze Bz-423 and its analogs in eliminating effector lymphocytes during GVHD 2. To determine the effects of Bz-423 on immunologic reconstitution 3. To analyze the impact of Bz-423 on key myeloid populations following BMT 4. To analyze the bioenergetic profiles of human PBMC populations after allogeneic BMT

项目摘要（请参阅说明）： 移植物与宿主疾病（GVHD）仍然是同种异体骨的主要且棘手的并发症 骨髓移植（BMT）。 GVHD的两个主要效应子机制是炎症细胞因子和 活化的淋巴细胞。在这个新项目中，我们探索了一种新颖的生物能策略来消除 GHVD中的淋巴细胞效应子。初步研究表明，在GVHD淋巴细胞中 宿主的组织相容性抗原长期激活具有异常的生物能谱。 与急性激活的淋巴细胞相比，GVHD效应子淋巴细胞的糖酵解水平较低 显示线粒体应激的迹象，包括活性氧水平升高（ROS）。效应子 淋巴细胞可以选择性地诱导用细胞毒性苯二氮卓类药物BZ-423诱导的凋亡 线粒体ATPase。 GVHD诱导后的7天开始给予BZ-423 单独的鼠标模型通过所有临床和组织学参数逆转GVHD，并显着 改善长期生存。该项目将研究BZ-423的分子机理 并探索其对血液学关键细胞亚群的生物能谱的影响 在这些动物模型中BMT后的免疫学重构。该项目还将定义 人类同种异体BMT的临床样品中白细胞亚群的生物能谱 收件人。我们的具体目的是： 1。分析BZ-423及其在消除GVHD期间消除效应子淋巴细胞的类似物 2。确定BZ-423对免疫重建的影响 3。分析BMT后BZ-423对关键髓样人群的影响 4。分析同种异体BMT后人类PBMC种群的生物能谱