Animal Model of Transmissable Neurofibromas

一个独特的动物系统，雀鲷，神经纤维瘤病（DNF），将被用来解决神经纤维瘤，恶性外周神经鞘瘤和色素瘤的发病机制的基本问题。在人类外周神经鞘肿瘤的发展过程中，控制雪旺细胞，神经束膜细胞和轴突改变的机制的研究可以通过使用动物模型来大大促进，在该动物模型中，这些肿瘤和肿瘤过程可以在体内和体外进行实验操作。DNF是由一种不寻常的、可传播的病毒样因子引起的，即Dansminus病毒样因子（DVLA），并且似乎是涉及任何神经外胚层的可传播肿瘤的唯一自然发生的例子，也是涉及任何神经外胚层来源的细胞类型的可传播肿瘤的唯一自然发生的例子。因此，该模型系统提供了一个独特的机会，在许多层面上的致癌过程的实验操作。目前正在进行的研究将通过四个相互关联的目标来解决与这种试剂的完整表征及其与这些神经外胚层细胞类型的肿瘤转化的关系相关的假设：（1）DVLA的完整序列和转录模式将被记录，DVLA基因组的感染性克隆将被创建。(2)将在体内和体外确定来自患病鱼的肿瘤和感染的非肿瘤细胞类型中DVLA复制的状态。(3)控制复制，转录，翻译和生产的感染性物质在体外的因素将被确定通过操纵细胞系慢性感染DVLA和开发感染试验系统。这些系统也将用于评估该试剂的分离株在体内的致瘤性。(4)将鉴定由DVLA表达的全部蛋白质，并开发针对所选病毒蛋白质的抗体。拟议的研究应产生信息的机制，肿瘤的发展在周围神经系统适用于了解这些过程中的人类疾病，如1型神经纤维瘤病。

A unique animal system , damselfish, neurofibromatosis (DNF), will be used to address basic questions in the pathogenesis of neurofibromas, malignant peripheral nerve sheath tumors and chromatophoromas. Investigation of the mechanisms controlling alterations of Schwann cells, perineurial cells and axons during the development of peripheral nerve sheath tumors in humans could be greatly facilitated by the use of an animal model in which these tumors and the neoplastic process could be manipulated experimentally, both in vivo and in vitro. DNF is caused by an unusual, transmissible, virus-like agent, the damselfish-virus like agent (DVLA), and appears to be the only naturally occurring example of a transmissible tumor involving any neuroectodermally the only naturally occurring example of a transmissible tumor involving any neuroectodermally derived cell type. Thus, this model system provides a unique opportunity for experimental manipulation of this carcinogenic process at many levels. Ongoing research on DNF will address hypotheses relevant to a complete characterization of this agent and its relationship to neoplastic transformation of these neuroectodermal cell types through four interrelated aims: (1) The complete sequence and transcriptional pattern of DVLA will be documented and infectious clones of the DVLA genome will be created. (2) The status of DVLA replication in tumors and infected non-tumor cell types from diseased fish will be determined in vivo and in vitro. (3) Factors controlling replication, transcription, translation and production of infectious material in vitro will be identified by manipulating cell lines chronically infected with DVLA and developing infection assay systems. These systems will also be used to assess the tumorigenicity of isolates of this agent in vivo. (4) The full range of proteins expressed by DVLA will be identified and antibodies developed to selected viral proteins. The proposed studies should yield information on mechanisms of tumor development in the peripheral nervous system applicable to understanding these processes in human disorders such as neurofibromatosis type 1.