PROLIFERATIVE CAPACITY AND RADIOBIOLOGY OF STEM CELLS

干细胞的增殖能力和放射生物学

• 批准号: 2376739
• 负责人: PETER M MAUCH
• 金额: $ 24.04万
• 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 1998-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2376739
• 关键词: autologous transplantation; bone marrow transplantation; cell growth regulation; cellular oncology; chemoprevention; combination cancer therapy; cytokine; cytotoxicity; hematopoiesis; hematopoietic growth factor; hematopoietic stem cells; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer radiation therapy; nonhuman therapy evaluation; radiation dosage; radiobiology; radioprotective agents; tissue /cell culture; whole body irradiation effect

DESCRIPTION: (Applicant's Abstract) The objectives of this 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 bone marrow transplantation (BMT) by optimizing donor engraftment and long-term recipient hematopoiesis. Autologous BMT is becoming increasingly important for treating a variety of benign and malignant disorders in the clinic. Yet, little is known of the effects of prior cytotoxic agent exposure on donor autologous hematopoietic stem cells (HSC), and of the effects of cytokines, used to speed recovery after cytotoxic agents or after BMT, on long-term hematopoiesis. Specific Aim 1 of this application will determine how cytotoxic agents and cytokines affect donor marrow and its capacity to provide short- and long-term hematopoiesis after lethal total body irradiation (TBI). Mobilized peripheral blood stem cells (PBSC) are increasingly being used for autologous stem cell transplantation because they can be collected without general anesthesia and result in more rapid engraftment than bone marrow stem cells (BMSC). Despite the wide clinical use of mobilized PBSC, very little is known of the mechanisms of mobilization or how mobilization varies with different techniques. Through Specific Aim 2 the applicant will study mechanisms of mobilization of HSC from the marrow to the blood. Host preparation for BMT with TBI or busulfan is associated with potential serious toxicity to nonhematopoietic organs. For autologous transplantation, especially when transplantation is being proposed for correction of genetic disorders, there may be an opportunity to use less toxic agents. The ability of stable mixed donor-recipient chimerism to provide successful functional reconstitution in patients transplanted with transduced autologous HSC, should allow opportunities to greatly reduce or eliminate conditioning with TBI. In Specific Aim 3, the applicant will develop novel techniques to maintain or enhance engraftment while utilizing reduced doses of systemic chemoradiotherapy. Mouse models offer many advantages over primates and other animals in studying hematopoiesis. The ability to measure host stem cell ablation by congenic markers, to study large numbers of animals, to evaluate transplantation across well defined genetic barriers, to evaluate donor primitive and progenitor cell engraftment by functional assays, to quantify long-term hematopoiesis through marrow repopulating studies, and to assess long- term toxicity allow questions to be addressed that cannot be answered in other animal systems or in humans. Most importantly, extensive studies in the mouse of BMSC, PBSC, engraftment, and host toxicity have proven to be excellent analogs for clinical studies. In this application, models developed in preliminary mouse studies should serve as guidelines to modification of clinical practice.

描述：（申请人的摘要）该项目的目标是 为了研究骨髓的干细胞室，其功能 组织，以及该组织对临床的影响 使用细胞毒性剂，细胞因子和辐射。这个项目也是 致力于改善自体骨髓移植（BMT） 通过优化供体植入和长期接受者造血。 自体BMT对于治疗一种品种越来越重要 诊所中的良性和恶性疾病。但是，知之甚少 先前的细胞毒性剂暴露对供体自体的影响 造血干细胞（HSC）和使用的细胞因子的作用 长期后，在细胞毒性剂或BMT之后加快恢复 造血。本应用程序的具体目标1将决定如何 细胞毒性剂和细胞因子会影响供体骨髓及其能力 致命总体后提供短期和长期造血 辐照（TBI）。动员的外周血干细胞（PBSC）为 越来越多地用于自体干细胞移植 可以在没有全身麻醉的情况下收集它们，并导致更多 比骨髓干细胞快速植入（BMSC）。尽管宽阔 动员PBSC的临床使用，对这些机制知之甚少 动员或动员如何随着不同的技术而变化。 通过特定目标2申请人将研究 HSC从骨髓动员到血液。主机准备 具有TBI或Busulfan的BMT与潜在的严重毒性有关 非杂造器官。用于自体移植，尤其是 当提出移植以纠正遗传时 疾病，可能有机会使用较少的有毒药物。这 稳定的混合供体 - 接收者嵌合提供成功的能力 通过转导的患者的功能重构 自体HSC，应允许机会大大减少或消除 用TBI调理。在特定目标3中，申请人将发展 利用时保持或增强植入的新技术 降低了全身性化学疗法的剂量。鼠标模型提供了许多 在研究造血性方面，优先动物和其他动物的优势。 通过相邻标记测量宿主干细胞消融的能力， 研究大量动物，以评估井的移植 定义的遗传障碍，以评估供体原始和祖先 通过功能分析植入细胞，以量化长期 造血通过骨髓再现研究，并评估长期 术语毒性允许解决无法回答的问题 在其他动物系统或人类中。最重要的是，广泛 在BMSC，PBSC，植入和宿主毒性的小鼠中的研究具有 被证明是用于临床研究的极好的类似物。在这个 应用，初步小鼠研究中开发的模型应服务 作为修改临床实践的指南。