Animal Model of Transmissable Neurofibromas

一个独特的动物系统，小雀鲷，神经纤维瘤病（DNF），将用于解决神经纤维瘤，恶性周围神经鞘肿瘤和色素瘤的发病机制的基本问题。在人类周围神经鞘肿瘤的发展过程中，雪旺细胞、神经周围细胞和轴突的变化控制机制的研究可以通过使用动物模型来极大地促进，在动物模型中，这些肿瘤和肿瘤过程可以在体内和体外实验中进行操纵。DNF是由一种不寻常的、可传播的病毒样因子——豆娘鱼病毒样因子（DVLA）引起的，似乎是唯一自然发生的涉及任何神经外胚层的传染性肿瘤的例子，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传染性肿瘤的例子。因此，这个模型系统提供了一个独特的机会，实验操作在许多层面上的致癌过程。正在进行的DNF研究将通过四个相互关联的目标来解决与该药物的完整表征及其与这些神经外胚层细胞类型的肿瘤转化关系相关的假设：(1)将记录DVLA的完整序列和转录模式，并创建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)在体外控制复制、转录、翻译和感染性物质产生的因素将通过操纵慢性感染DVLA的细胞系和开发感染检测系统来确定。这些系统也将用于评估该制剂分离物在体内的致瘤性。(4)将鉴定DVLA表达的全系列蛋白，并针对选定的病毒蛋白开发抗体。拟议的研究应提供肿瘤在周围神经系统发展机制的信息，适用于理解人类疾病（如1型神经纤维瘤病）的这些过程。

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.