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

项目总结（见说明）： 移植物抗宿主病（GVHD）仍然是同种异体骨的主要和难治性并发症 骨髓移植（BMT）。GVHD的两种主要效应机制是炎性细胞因子和 活化淋巴细胞在这个新项目中，我们探索了一种新的生物能量策略， GHVD中的淋巴细胞效应物。初步研究表明，在GVHD过程中， 被宿主的组织相容性抗原慢性激活的细胞具有异常的生物能量谱。 与急性活化的淋巴细胞相比，GVHD效应淋巴细胞具有低水平的糖酵解， 显示线粒体应激的迹象，包括活性氧（ROS）水平升高。执行器 淋巴细胞可被细胞毒性苯二氮卓类药物Bz-423选择性诱导为果糖， 线粒体ATP酶。Bz-423的施用在两个小鼠中诱导GVHD后7天开始。 单独的小鼠模型通过所有临床和组织学参数逆转GVHD，并且显著地 提高长期生存率。本项目将研究Bz-423的分子作用机制 并探讨其对血液学过程中关键细胞亚群生物能量谱的影响。 以及骨髓移植后免疫重建的研究。该项目还将定义 人类异基因骨髓移植临床样本中白细胞亚群的生物能谱 受惠人士我们的具体目标是： 1.分析Bz-423及其类似物在GVHD中清除效应淋巴细胞的作用 2.确定Bz-423对免疫重建的影响 3.分析Bz-423对BMT后关键髓系人群的影响 4.分析异基因BMT后人PBMC群的生物能量谱