Neuronal Transplants as an Organotypic Brain Tumor Model

描述（由申请人提供）： 通过将成年大鼠和出生后人尸体的多能神经前体异种移植到免疫缺陷小鼠中，将建立CNS发育和肿瘤的器官型模型。对这些神经前体的初步研究将在体外进行，以记录不对称细胞分裂，以确定这是否与细胞命运的不对称分布有关，并确定不对称细胞分裂的蛋白质决定因素。候选决定簇已经根据它们与果蝇中遗传鉴定的决定簇的同源性来鉴定。将使用免疫细胞化学方法来确定这些同源物是否在体外和器官型模型的不对称分裂过程中显示出不对称和动态分布，正如果蝇模型所预期的那样。候选决定因素包括肿瘤抑制因子Dlg及其结合伴侣Pins，它们是在本实验室发现的，是父母资助的主要焦点。结果将显示这种器官型模型是否允许正常CNS的典型分裂和发育模式，以及它是否是研究人类干细胞发育和CNS肿瘤中出现的细胞异常的有用系统。最终，它可能被用来探索包括基因治疗和药物治疗在内的治疗策略的有效性。

DESCRIPTION (provided by applicant): An organotypic model for CNS development and tumors will be established by xenotransplantation of multi-potent neural precursors from adult rats and from postnatal human cadavers into immune-deficient mice. Initial studies on these neural precursors will be carried out in vitro in order to document asymmetric cell division, to determine whether this is associated with asymmetric distribution of cell fates, and to identify the protein determinants of asymmetric cell division. Candidate determinants have been identified based on their homology with determinants identified genetically in Drosophila. Immunocytochemical methods will be used to determine whether these homologs show asymmetric and dynamic distribution during asymmetric division in vitro and in the organotypic model, as expected from the Drosophila model. Candidate determinants include the tumor suppressor Dlg and its binding partner Pins, which were discovered in this laboratory and are the main focus of the parent grant. The results will show whether this organotypic model allows division and development patterns typical of normal CNS, and whether it is a useful system in which to investigate the development of human stem cells and the cellular abnormalities arising in CNS tumors. Eventually it may be possible to use it to explore the effectiveness of therapeutic strategies including gene therapy and drug treatments.