Zielzellen insertioneller Transformation in der Hämatopoese

造血插入转化的靶细胞

• 批准号: 22771052
• 负责人: Professor Dr. Christopher Baum
• 金额: --
• 依托单位: Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/22771052?language=en
• 关键词: Zielzellen; insertioneller; Transformation; der; matopoese

Increasing evidence reveals that random insertion of gene transfer vectors into the genome of hematopoietic cells may have substantial consequences for their differential clonal selection in vivo. Clonal dominance triggered by retroviral vector insertions in (the vicinity of) proto-oncogenes or other signalling genes has been described for both normal and malignant hematopoiesis. However, it is unknown to what extent the outcome of insertional mutagenesis as a side effect of somatic \ transgenesis is related to (1) mtrinsinc properties of the target cell, (2) extrinsic environmental factors influencing clonal competition in vivo, and (3) the type of transgene vectors. The present proposal addresses these questions in murine models of bone marrow transplantation (BMT), hypothesizing that clonal selection within the organism may originate from otherwise short-lived progenitor cells and is promoted by milieu conditions of stress hematopoiesis and suboptimal vector technology. Our work may provide a rationale for the improved design of clinical trials in gene therapy and generate new insights into fundamental processes of cellular self-renewal and transformation.

越来越多的证据表明，基因转移载体的随机插入到造血细胞的基因组可能会产生实质性的后果，其差异克隆选择在体内。逆转录病毒载体插入原癌基因或其他信号基因（附近）引发的克隆优势已被描述为正常和恶性造血。然而，作为体细胞转基因的副作用，插入突变的结果在多大程度上与（1）靶细胞的转基因特性，（2）影响体内克隆竞争的外部环境因素和（3）转基因载体的类型有关还不清楚。目前的建议解决了这些问题，在小鼠模型的骨髓移植（BMT），假设生物体内的克隆选择可能源于其他短寿命的祖细胞，并促进应激造血和次优载体技术的环境条件。我们的工作可能为基因治疗临床试验的改进设计提供理论基础，并对细胞自我更新和转化的基本过程产生新的见解。