Animal Model of Transmissable Neurofibromas

在神经纤维瘤、恶性周围神经鞘瘤和色素瘤的发病机制中，将使用一种独特的动物系统，即神经纤维瘤、神经纤维瘤和色素瘤。研究人类周围神经鞘肿瘤发展过程中雪旺细胞、神经周围细胞和轴突变化的控制机制，可以通过体内和体外的实验操作这些肿瘤和肿瘤过程的动物模型来极大地促进。DNF是由一种不寻常的、可传播的、类病毒的病毒剂(DVLA)引起的，并且似乎是唯一自然发生的涉及任何神经外胚层的可传播肿瘤病例，也是唯一自然发生的涉及任何神经外胚层衍生细胞类型的可传播肿瘤病例。因此，该模型系统为在多个水平上对这一致癌过程进行实验操作提供了一个独特的机会。正在进行的关于DNF的研究将通过四个相互关联的目标来解决与这种药物的完整特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)将记录DVLA的完整序列和转录模式，并将创建DVLA基因组的感染性克隆。(2)将在体内和体外确定DVLA在肿瘤和病鱼感染的非肿瘤细胞类型中的复制状态。(3)通过操纵慢性感染DVLA的细胞系和建立感染检测系统，将在体外识别控制感染性物质的复制、转录、翻译和产生的因素。这些系统也将被用来评估这种药物的分离株在体内的致瘤性。(4)将鉴定DVLA表达的所有蛋白质，并针对选定的病毒蛋白质开发抗体。这项拟议的研究应该会提供关于周围神经系统肿瘤发展机制的信息，这些信息适用于理解人类疾病的这些过程，如神经纤维瘤病1型。

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.