PROLIFERATIVE CAPACITY AND RADIOBIOLOGY OF STEM CELLS

干细胞的增殖能力和放射生物学

• 批准号: 2085925
• 负责人: PETER M MAUCH
• 金额: $ 22.27万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-09-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2085925
• 关键词: autologous transplantation; bone marrow transplantation; cell differentiation; cell growth regulation; cellular oncology; chemoprevention; colony stimulating factor; combination cancer therapy; cyclophosphamide; cytotoxicity; drug adverse effect; hematopoiesis; hematopoietic growth factor; hematopoietic stem cells; interleukin 1; interleukin 3; interleukin 6; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer radiation therapy; nonhuman therapy evaluation; radiation dosage; radiobiology; radioprotective agents; synchronous cell division; tissue /cell culture; whole body irradiation effect

The bone marrow is an important dose-limiting cell renewal tissue for chemotherapy, radiation therapy, and bone marrow transplantation (BMT). The objectives of this ongoing project are to study the stem cell compartment of the bone marrow, its functional organization, and the implications of this organization on the clinical use of cytotoxic agents, cytokines, and radiation. This project is also directed toward improving autologous BMT by optimizing donor marrow engraftment and long-term hematopoiesis and survival of recipients. To continue these objectives we will characterize donor marrow stem cell subpopulations responsible for providing short-term engraftment and long-term hematopoiesis after transplantation, evaluate the ability of selected radioprotective and chemoprotective agents to protect the earliest stem cells, and define the effects of high dose cytotoxic agents and TBI on the host stem cells and microenvironment. Re-establishment of normal hematopoiesis following BMT occurs in two phases. Initial recovery of peripheral blood counts appears to be mediated by late stem and progenitor cells. Long-term maintenance of hematopoiesis is due to more primitive stem cells. Many autologous BMT candidates have had extensive prior exposure to chemotherapy which may damage these subpopulations. Using a murine autologous BMT model and both in vivo and in vitro stem cell assays, we will determine the relationship between changes in stem cell subpopulation distribution and ability to engraft and provide long-term hematopoiesis and recipient survival for donor marrows previously exposed to various cytotoxic agents. Cytokine therapy is becoming increasingly utilized to speed hematopoietic recovery after high dose chemotherapy and BMT. Studies will be performed to evaluate the effects of four cytokines (I.-1, IL-3, IL-6, and G-CSF) on bone marrow stem cell content and self-renewal following chemotherapy or BMT. Some of these cytokines also demonstrate radioprotective effects on the bone marrow. The radioprotective capacity of IL-1 and G-CSF for primitive stem cells will be evaluated. AcSDKP, an inhibitory synthetic tetrapeptide, has been shown to protect hematopoietic stem cells from cycle-active drugs. This agent will be further investigated for its ability to protect primitive marrow stem cells from radiotherapy and other cytotoxic agents. The acute myelotoxicity following high dose TBI, chemotherapy, or radioimmunotherapy regimens used to treat patients with advanced malignancies can be circumvented by autologous bone marrow rescue. The influence of these treatment regimens on the earliest host stem cells, on the supporting microenvironment, and on donor marrow engraftment will be determined. Little is known of the factors most important for obtaining long-term engraftment of autologous donor marrow in the clinic. This is due to the lack of a primitive stem cell assay for human marrow, and the absence of markers to measure autologous marrow engraftment. Most high dose chemotherapy programs do not totally ablate the host hematopoietic stem cells, and it is not known whether residual host or engrafted donor hematopoietic stem cells provide the host with long-term hematopoietic support. The ability to directly measure host stem cell ablation, and to evaluate the quality of donor marrow engraftment by self-renewal and survival assays in the mouse should provide answers to many questions concerning autologous BMT in the clinic.

骨髓是重要的剂量限制细胞更新组织 化学疗法，放射治疗和骨髓移植（BMT）。 这个正在进行的项目的目标是研究干细胞 骨髓，其功能组织和 该组织对细胞毒性剂的临床使用的影响， 细胞因子和辐射。 该项目也用于改善 通过优化供体骨髓植入和长期的自体BMT 造血和接受者的存活。 为了继续这些目标，我们 将表征负责的供体骨髓干细胞亚群 提供短期植入和长期造血作用 移植，评估选定的辐射保护和 化学保护剂以保护最早的干细胞，并定义 高剂量的细胞毒性剂和TBI对宿主干细胞和 微环境。 BMT后重新建立正常造血作用 发生在两个阶段。 出现外周血计数的初步恢复 由晚期和祖细胞介导。 长期维护 造血是由于更原始的干细胞引起的。 许多自体BMT 候选人已有广泛的事先接触化学疗法，这可能 损害这些亚群。 使用鼠自体BMT模型，两者都使用 体内和体外干细胞分析，我们将确定关系 在干细胞亚群分布的变化与能力之间 植入并提供长期造血和接受者的生存 供体骨髓先前暴露于各种细胞毒性剂。 细胞因子 治疗越来越多地用于加快造血恢复 高剂量化疗和BMT之后。 研究将进行 评估四种细胞因子（I.-1，IL-3，IL-6和G-CSF）的影响 化学疗法后的骨髓干细胞含量和自我更新 BMT。 这些细胞因子中的一些也表现出对辐射保护作用 骨髓。 IL-1和G-CSF的辐射保护能力 将评估原始干细胞。 ACSDKP，一种抑制性合成 四肽已被证明可以保护造血干细胞免受 周期活性药物。 该代理将进一步调查 保护原始骨髓干细胞免受放疗和其他 细胞毒性剂。 高剂量TBI后的急性骨髓毒性， 化学疗法或放射免疫治疗方案用于治疗患者 自体骨髓救援可以规避晚期恶性肿瘤。 这些治疗方案对最早宿主干细胞的影响， 在支持的微环境中，在捐赠者骨髓植入术上将是 决定。 对获得最重要的因素知之甚少 诊所中自体供体骨髓的长期植入。 这是 由于缺乏针对人骨髓的原始干细胞测定法，而 缺乏标记来测量自体骨髓植入。 最高 剂量化学疗法计划不会完全消除宿主造血 干细胞，尚不清楚残留宿主还是植入供体 造血干细胞为宿主提供长期造血 支持。 直接测量宿主干细胞消融的能力，并 通过自我更新和 鼠标中的生存测定应为许多问题提供答案 关于诊所中的自体BMT。